TRPA1 modulators

ABSTRACT

This disclosure relates to polycyclic heteroaromatic compounds useful as TRPA1 modulators, as well as compositions and methods of treating pain that include the compounds.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application, U.S. patent application Ser. No. 15/909,652,was filed on Mar. 1, 2018 as a continuation of U.S. patent applicationSer. No. 15/203,774, which was filed on Jul. 6, 2016 as acontinuation-in-part that claims the priority of International PatentApplication No. PCT/US2014/7229 (filed Dec. 23, 2014), which claims thepriority of U.S. Provisional Patent Application No. 61/924,119 (filedJan. 6, 2014). U.S. patent application Ser. Nos. 15/909,652 and15/203,774 and International Patent Application No. PCT/US2014/7229 areincorporated herein by reference in their entirety.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

This invention was made with government support under grant1R43DA031516, awarded by National Institute on Drug Abuse. The U.S.government has certain rights in the invention.

REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED ON A COMPACT DISK

This application includes a Sequence Listing as a text file named“AMDX-01-0116USC1_2018-03-01_US15909652_SEQLIST,” created Mar. 1, 2018,and containing 66,956 bytes. The material contained in this text file isincorporated by reference in its entirety for all purposes.

FIELD OF THE INVENTION

This disclosure relates to TRPA1-modulating compounds useful fortreating pain as well as compositions and methods that include thecompounds. In some embodiments, the compounds of the present inventionhave applications in preventing, reducing or inhibiting acute or chronicpain in a variety of operative and interventional procedures, includingsurgical, diagnostic and therapeutic procedures.

BACKGROUND OF THE INVENTION

More than 100 million Americans suffer from chronic pain. Furthermore,problems with use of illicit drugs include pain-reliever misuse, abuse,and addiction. Because of this, it is increasingly difficult forpatients with legitimate medical needs for opioid-containing drugs, likeVicodin, to obtain prescriptions. The U.S. Substance Abuse and MentalHealth Services Administration estimated 20.1 million Americans wereillicit-drug users and an estimated 4.7 million of those persons usedpain relievers non-medically in 2008. Thus, an effective treatment forchronic pain that has less addictive potential and abuse liability is amajor unmet need in medicine today.

Transient receptor potential cation channel, subfamily A, member 1,(“TRPA1”; wild-type, SEQ ID NO:1; variants, SEQ ID NOS:2-7) is anon-selective cation channel present in mammalian cells.TRPA1-receptor/channels play a highly specific function in sensorynerves that transmit the sensations of pain and hyperalgesia in responseto inflammation as well as nerve injury, particularly in chronicconditions. Recent progress in understanding the function andidentification of endogenous ligands for TRPA1 channels suggests thatTRPA1 is relevant to detecting nociceptive signals.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the invention provides a compound of Formula I:

-   -   or a pharmaceutically acceptable salt thereof;        wherein:    -   A is a cyclic group of Formula Ia:

-   -   -   wherein Z¹, Z², Z³, Z⁴, Z⁵, and Z⁶ are each a member            selected from the group consisting of N, CH, CR^(a), and            NR^(c); or, alternatively for Z¹ or Z⁶, the member Z¹ or Z⁶            and X, together with atoms in the rings to which they are            attached, form an additional fused, five- to eight-membered            cycloalkyl or heterocyclyl ring with from 0 to 4 R^(z)            substituents;        -   with the proviso that at least one member selected from the            group consisting of Z², Z³, Z⁴, and Z⁶ is N;

    -   each R^(z) is a member independently selected from the group        consisting of halo, C₁-C₃ alkyl, C₁-C₃ haloalkyl, and C₁-C₃        alkoxy; or, alternatively, two R^(z) substituents, together with        the carbon atom to which they are attached, join to form an oxo,        spirocycloalkyl, or spiroheterocyclyl group;

    -   B is a cyclic group of Formula Ib:

-   -   -   wherein Y¹, Y², Y³, Y⁴, and Y⁵ are each a member            independently selected from the group consisting of N, CH,            and CR^(b); or, alternatively, the members —Y²═Y³— or            —Y⁴═Y⁵— are combined into a single member selected from the            group consisting of NR^(c), O, and S;

    -   each R^(a) and R^(b) is a member independently selected from the        group consisting of cyano, carboxyl, C₁-C₄ alkyl, C₁-C₄        hydroxyalkyl, C₃-C₈ cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,        C₁-C₄ haloalkoxy, halo, C₀-C₆ amino, C₁-C₆ amido, C₁-C₄        alkyloxycarbonyl, C₁-C₆ alkylsulfonyl, and hydroxyl; or,        alternatively, two adjacent R^(a) or R^(b), together with the        atoms in groups A or B to which they are attached, form an        additional fused aryl, heteroaryl, cycloalkyl, or heterocyclyl        ring with from 0 to 4 R^(z) substituents;

    -   each R^(c) is a member independently selected from the group        consisting of hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆        cycloalkyl, (C₃-C₆ cycloalkyl)C₁-C₃alkyl, and C₁-C₇ acyl;

    -   each u is an integer independently selected from 0 to 4;

    -   v is an integer from 0 to 5;

    -   X is N or CR^(d); or, alternatively, X is CR^(d), wherein X and        the member Z¹, together with atoms in the rings in which they        are included, form the additional fused, five- to eight-membered        cycloalkyl or heterocyclyl ring with from 0 to 4 R^(z)        substituents;

    -   each R^(d) is a member independently selected from the group        consisting of halo, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄        alkoxy, C₁-C₄ haloalkoxy, C₃-C₆ cycloalkyl, and C₃-C₆        cycloalkoxy;

    -   each L¹, L², and L³, if present, is a member independently        selected from the group consisting of C═O, C═S, and C═NR^(c);

    -   C is a cyclic group of Formula Ic:

-   -   -   wherein Q is a member selected from the group consisting of            C(R^(e))(D), N(E), F, and G; or, alternatively, the members            —W³-Q- or —W⁴-Q- join to form a member H; and        -   wherein W¹, W², W³, and W⁴ are each an independently            selected C(R^(f))₂; or, alternatively, the members —W³-Q- or            —W⁴-Q- join to form a member H;

    -   R^(e) is a member selected from the group consisting of        hydrogen, C₁-C₃ alkyl, and C₁-C₃ fluoroalkyl; or, alternatively,        R^(e) and an R^(f) substituent of W¹, W², W³, or W⁴ join to form        a —(C(R^(z))₂)_(t)— bridge, wherein t is an integer selected        from 2 or 3;

    -   each R^(f) is a member independently selected from the group        consisting of hydrogen, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, and        halo; or, alternatively, two adjacent R^(f), together with the        atoms in group C to which they are attached, form an additional        aryl, heteroaryl, cycloalkyl, or heterocyclyl fused ring with        from 0 to 4 R^(z) substituents; or, alternatively, two geminal        R^(f), together with the atom in group C to which they are        attached, form a spirocycloalkyl or spiroheterocyclyl ring with        from 0 to 4 R^(z) substituents; or, alternatively, two axial        R^(f) substituents of a pair of W^(n) selected from the group        consisting of (W¹ and W²), (W² and W³), and (W³ and W⁴) join to        form a —(C(R^(z))₂)_(t)— bridge; or, alternatively, R^(e) and an        R^(f) substituent of W¹, W², W³, or W⁴ join to form a        —(C(R^(z))₂)_(t)— bridge;

    -   each t is an integer selected from 2 or 3;

    -   D is a bicyclic group of Formula Id:

-   -   E is a bicyclic group of Formula Ie:

-   -   F is a spirocyclic group of Formula If:

-   -   G is a bicyclic spirocyclic group of Formula Ig:

-   -   H is a fused group of Formula Ih:

-   -   -   wherein the H ring is a fused, five- to eight-membered            cycloalkyl or heterocyclyl ring;        -   wherein v is an integer from 0 to 4; and        -   wherein w is an integer from 0 to 2; and

-   Y⁶, Y⁷, Y⁸, Y⁹, and Y¹⁰, if present, are each a member independently    selected from the group consisting of N, CH, and CR^(b); or,    alternatively for Y⁸ and Y⁹, the members —Y⁶═Y⁷— or —Y⁸═Y⁹— are    combined into a single member selected from the group consisting of    NR^(c), O, and S.

In one preferred aspect, the invention provides a compound of Formula I:

-   -   or a pharmaceutically acceptable salt thereof;        wherein:    -   A is a cyclic group of Formula Ia:

-   -   -   wherein Z¹, Z², Z³, Z⁴, and Z⁵ are each a member selected            from the group consisting of N, CH, and CR^(a); or,            alternatively for Z¹, the member Z¹ and X, together with            atoms in the rings to which they are attached, form an            additional fused, five- to eight-membered cycloalkyl or            heterocyclyl ring with from 0 to 4 R^(z) substituents;        -   with the proviso that at least one member selected from the            group consisting of Z², Z³, and Z⁴ is N;

    -   each R^(z) is a member independently selected from the group        consisting of halo, C₁-C₃ alkyl, C₁-C₃ haloalkyl, and C₁-C₃        alkoxy; or, alternatively, two R^(z) substituents, together with        the carbon atom to which they are attached, join to form an oxo,        spirocycloalkyl, or spiroheterocyclyl group;

    -   B is a cyclic group of Formula Ib:

-   -   -   wherein Y¹, Y², Y³, Y⁴, and Y⁵ are each a member            independently selected from the group consisting of N, CH,            and CR^(b); or, alternatively, the members —Y²═Y³— or            —Y⁴═Y⁵— are combined into a single member selected from the            group consisting of NR^(c), O, and S;

    -   each R^(a) and R^(b) is a member independently selected from the        group consisting of cyano, carboxyl, C₁-C₄ alkyl, C₁-C₄        hydroxyalkyl, C₃-C₈ cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,        C₁-C₄ haloalkoxy, halo, C₀-C₆ amino, C₁-C₆ amido, C₁-C₄        alkyloxycarbonyl, C₁-C₆ alkylsulfonyl, and hydroxyl; or,        alternatively, two adjacent R^(a) or R^(b), together with the        atoms in groups A or B to which they are attached, form an        additional fused aryl, heteroaryl, cycloalkyl, or heterocyclyl        ring with from 0 to 4 R^(z) substituents;

    -   each R^(c) is a member independently selected from the group        consisting of hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆        cycloalkyl, (C₃-C₆ cycloalkyl)C₁-C₃alkyl, and C₁-C₇ acyl;

    -   each u is an integer independently selected from 0 to 4;

    -   v is an integer from 0 to 5;

    -   X is N or CR^(d); or, alternatively, X is CR^(d), wherein X and        the member Z¹, together with atoms in the rings in which they        are included, form the additional fused, five- to eight-membered        cycloalkyl or heterocyclyl ring with from 0 to 4 R^(z)        substituents;

    -   each R^(d) is a member independently selected from the group        consisting of hydrogen, halo, cyano, C₁-C₄ alkyl, C₁-C₄        haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₃-C₆ cycloalkyl, and        C₃-C₆ cycloalkoxy;

    -   each L¹, L², and L³, if present, is a member independently        selected from the group consisting of C═O, C═S, and C═NR^(c);

    -   C is a cyclic group of Formula Ic:

-   -   -   wherein Q is a member selected from the group consisting of            C(R^(e))(D), N(E), F, and G; or, alternatively, the members            —W³-Q- or —W⁴-Q- join to form a member H; and        -   wherein W¹, W², W³, and W⁴ are each an independently            selected C(R^(f))₂; or, alternatively, the members —W³-Q- or            —W⁴-Q- join to form a member H;

    -   R^(e) is a member selected from the group consisting of        hydrogen, C₁-C₃ alkyl, and C₁-C₃ fluoroalkyl; or, alternatively,        R^(e) and an R^(f) substituent of W¹, W², W³, or W⁴ join to form        a —(C(R^(z))₂)_(t)— bridge, wherein t is an integer selected        from 2 or 3;

    -   each R^(f) is a member independently selected from the group        consisting of hydrogen, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, and        halo; or, alternatively, two adjacent R^(f), together with the        atoms in group C to which they are attached, form an additional        aryl, heteroaryl, cycloalkyl, or heterocyclyl fused ring with        from 0 to 4 R^(z) substituents; or, alternatively, two geminal        R^(f), together with the atom in group C to which they are        attached, form a spirocycloalkyl or spiroheterocyclyl ring with        from 0 to 4 R^(z) substituents; or, alternatively, two axial        R^(f) substituents of a pair of W^(n) selected from the group        consisting of (W¹ and W²), (W² and W³), and (W³ and W⁴) join to        form a —(C(R^(z))²)_(t)— bridge; or, alternatively, R^(e) and an        R^(f) substituent of W¹, W², W³, or W⁴ join to form a        —(C(R^(z))₂)_(t)— bridge;

    -   each t is an integer selected from 2 or 3;

    -   D is a bicyclic group of Formula Id:

-   -   E is a bicyclic group of Formula Ie:

-   -   F is a spirocyclic group of Formula If:

-   -   G is a bicyclic spirocyclic group of Formula Ig:

-   -   H is a fused group of Formula Ih:

-   -   -   wherein the H ring is a fused, five- to eight-membered            cycloalkyl or heterocyclyl ring;        -   wherein v is an integer from 0 to 4; and        -   wherein w is an integer from 0 to 2; and

-   Y⁶, Y⁷, Y⁸, Y⁹, and Y¹⁰, if present, are each a member independently    selected from the group consisting of N, CH, and CR^(b); or,    alternatively for Y⁸ and Y⁹, the members —Y⁶═Y⁷— or —Y⁸═Y⁹— are    combined into a single member selected from the group consisting of    NR^(c), O, and S.

In one aspect, the invention provides a compound of Formula II:

-   -   or a pharmaceutically acceptable salt thereof;        wherein:    -   A is a cyclic group of Formula IIa:

-   -   -   wherein Z¹, Z², Z³, Z⁴, and Z⁵ are each a member selected            from the group consisting of N, CH, and CR^(a); or,            alternatively for Z¹, the member Z¹ and X, together with            atoms in the rings to which they are attached, form an            additional fused, five- to eight-membered cycloalkyl or            heterocyclyl ring with from 0 to 5 R^(z) substituents;        -   with the proviso that at least one member selected from the            group consisting of Z², Z³, and Z⁴ is N;

    -   each R^(z) is a member independently selected from the group        consisting of halo, C₁-C₃ alkyl, C₁-C₃ haloalkyl, and C₁-C₃        alkoxy; or, alternatively, two R^(z) substituents, together with        the carbon atom to which they are attached, join to form an oxo,        spirocycloalkyl, or spiroheterocyclyl group;

    -   B is a cyclic group of Formula IIb:

-   -   -   wherein Y¹, Y², Y³, Y⁴, and Y⁵ are each a member            independently selected from the group consisting of N, CH,            and CR^(b); or, alternatively, the members —Y²═Y³— or            —Y⁴═Y⁵— are combined into a single member selected from the            group consisting of NR^(c), O, and S;

    -   each R^(a) and R^(b) is a member independently selected from the        group consisting of cyano, carboxyl, C₁-C₄ alkyl, C₁-C₄        hydroxyalkyl, C₃-C₈ cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,        C₁-C₄ haloalkoxy, halo, C₀-C₆ amino, C₁-C₆ amido, C₁-C₄        alkyloxycarbonyl, C₁-C₆ alkylsulfonyl, and hydroxyl; or,        alternatively, two adjacent R^(a) or R^(b), together with the        atoms in groups A or B to which they are attached, form an        additional fused aryl, heteroaryl, cycloalkyl, or heterocyclyl        ring with from 0 to 5 R^(z) substituents;

    -   each R^(c) is a member independently selected from the group        consisting of hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆        cycloalkyl, (C₃-C₆ cycloalkyl)C₁-C₃alkyl, and C₁-C₇ acyl;

    -   each u is an integer independently selected from 0 to 4;

    -   v is an integer from 0 to 5;

    -   X is N or CR^(d); or, alternatively, X is CR^(d), wherein X and        the member Z¹, together with atoms in the rings in which they        are included, form the additional fused, five- to eight-membered        cycloalkyl or heterocyclyl ring with from 0 to 5 R^(z)        substituents;

    -   each R^(d) is a member independently selected from the group        consisting of halo, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄        alkoxy, C₁-C₄ haloalkoxy, C₃-C₆ cycloalkyl, and C₃-C₆        cycloalkoxy;

    -   L¹ is a member selected from the group consisting of C═O, C═S,        and C═NR^(c);

    -   Y⁶, Y⁷, Y⁸, Y⁹, and Y¹⁰, if present, are each a member        independently selected from the group consisting of N, CH, and        CR^(b); or, alternatively for Y⁸ and Y⁹, the members —Y⁶═Y⁷— or        —Y⁸═Y⁹— are combined into a single member selected from the        group consisting of NR^(c), O, and S.

In another aspect, the invention provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of Formula Ior II and at least one pharmaceutically acceptable carrier, excipient,or diluent.

In another aspect, the invention provides a method of treating orpreventing pain comprising administering to a patient in need thereof atherapeutically effective amount, or a prophylactically effectiveamount, of a compound of Formula I or II.

Certain other aspects and embodiments of the present invention are setforth herein and will be apparent to those of skill in the art.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the paw withdrawal threshold (PWT in g) observed in ratstreated with a compound of the invention after spinal nerve ligation.

FIG. 2 shows the percentage of maximal possible effect (% MPE) of acompound of the invention in reducing neuropathic pain, as observed inrats treated with the compound after spinal nerve ligation.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. Definition of standard chemistry terms may be found in referenceworks, including Carey and Sundberg (2007) Advanced Organic Chemistry5^(th) Ed. Vols. A and B, Springer Science+Business Media LLC, New York.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the context clearly dictates otherwise. For example, anembodiment including “a TRPA1-modulating compound and an excipient”should be understood to present certain aspects with at least a secondTRPA1-modulating compound, at least a second excipient, or both.

The practice of the present invention will employ, unless otherwiseindicated, conventional methods of synthetic organic chemistry, massspectroscopy, preparative and analytical methods of chromatography,protein chemistry, biochemistry, recombinant DNA techniques andpharmacology. Conventional methods of organic chemistry include thoseincluded in March's Advanced Organic Chemistry: Reactions, Mechanisms,and Structure, 6^(th) Edition, M. B. Smith and J. March, John Wiley &Sons, Inc., Hoboken, N.J., 2007. Although methods and materials similaror equivalent to those described herein can be used in the practice ortesting of the present invention, suitable methods and materials aredescribed below. The materials, methods, and examples are illustrativeonly and not intended to be limiting.

The term “about” as used herein to modify a numerical value indicates adefined range around that value. If “X” were the value, “about X” wouldgenerally indicate a value from 0.95X to 1.05X. Any reference to “aboutX” specifically indicates at least the values X, 0.95X, 0.96X, 0.97X,0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Thus, “about X” isintended to teach and provide written description support for a claimlimitation of, e.g., “0.98X.” When the quantity “X” only includeswhole-integer values (e.g., “X carbons”), “about X” indicates from (X−1)to (X+1). In this case, “about X” as used herein specifically indicatesat least the values X, X−1, and X+1.

When “about” is applied to the beginning of a numerical range, itapplies to both ends of the range. Thus, “from about 5 to 20%” isequivalent to “from about 5% to about 20%.” When “about” is applied tothe first value of a set of values, it applies to all values in thatset. Thus, “about 7, 9, or 11%” is equivalent to “about 7%, about 9%, orabout 11%.”

The term “acyl” as used herein includes an alkanoyl, aroyl,heterocycloyl, or heteroaroyl group as defined herein. Examples of acylgroups include, but are not limited to, acetyl, benzoyl, and nicotinoyl.

The term “agonist” embraces agents that, e.g., increase, hasten, oractivate the expression of a described target protein or bind to,stimulate, increase, open, activate, enhance, increase activation,sensitize or up-regulate the activity of one or more proteins (orencoding polynucleotide(s)). As used herein, “agonist” generallyincludes partial agonists, full agonists, and superagonists (i.e.,greater than full agonism). Assays for determining whether a compound“agonizes” or “does not agonize” a protein include, e.g., contacting theprotein(s) with the compound and then determining the functional effectson the protein activity or contacting cells expressing protein(s) withthe compound and then determining the functional effects on thedescribed target protein activity. One of skill in the art will be ableto determine whether an assay is suitable for determining whether acompound agonizes or does not agonize a protein. Samples or assayscomprising a TRPA1 target are treated with a test compound and arecompared to control samples without the test compound (and to positivecontrol samples activated by exposure to a known TRPA1 agonist) tomeasure the extent of effect on TRPA1 activity. Control samples(untreated with agonists) are used to establish a baseline activityvalue. Agonism of the TRPA1 protein or channel is achieved when theactivity value increases relative to the untreated control (e.g.,increases by 20%, 30%, 40%, 50%, 75%, or 100%, or even more).

The term “antagonist” embraces agents that, e.g., slow or reduce theexpression of a described target protein or block, destimulate,decrease, close, deactivate, interfere with, reduce activation,desensitize or down-regulate the activity of one or more proteins (orencoding polynucleotide(s)). As used herein, “antagonist” generallyincludes partial antagonists and full antagonists. Assays fordetermining whether a compound “antagonizes” or “does not antagonize” aprotein include, e.g., contacting the protein(s) with the test compoundand then determining the functional effects on the protein activity orcontacting cells expressing protein(s) with the test compound and thendetermining the functional effects on the described target proteinactivity. One of skill in the art will be able to determine whether anassay is suitable for determining whether a compound antagonizes or doesnot antagonize a protein. Samples or assays comprising a TRPA1 targetare treated with a putative antagonist and are compared to controlsamples without the compound (and to control samples activated by aknown agonist) to measure the extent of effect on TRPA1 activity.Agonist-activated control samples (untreated with antagonists) areassigned a relative activity value of 100%. Antagonism of the TRPA1protein or channel activity is achieved when the activity value relativeto the agonist-activated control is less than 100% (e.g., 80%, 50%, 40%,30%, 20%, or 10%, or even lower).

Cells used to determine the agonist or antagonist activity of a compoundof the present invention can be cells or cell lines transiently orpermanently transfected or transformed with the appropriate nucleic acidencoding TRPA1 or can be cells or cell lines that express TRPA1 fromendogenous genes. Typically, the TRPA1 receptor-channel is expressed onthe surface of a recombinant host cell such as human embryonic kidney(HEK), CHO, SH-SY5Y or COS-7 cells. Alternatively, cells endogenouslyexpressing TRPA1, such as dorsal root ganglion neurons can be isolatedfrom an animal, cultured and used to determine antagonist activity.Examples of cell lines that endogenously express TRPA1 that are suitablefor use also include, but are not limited to the human WI-38 cell line,the differentiated human neuroblastoma IMR-32 cell line and thedifferentiated rat PC12 cell line. The assays described herein can alsobe performed with cells that express variant TRPA1 proteins. Methods forperforming assays to determine if a compound is an agonist or antagonistof the TRPA1 channel are well known in the art. One non-limiting exampleinvolves a spectrofluorometric assay in which cells loaded with afluorescent dye which is sensitive to intracellular calciumconcentrations are subsequently contacted with the compounds of interestto determine their ability to alter intracellular calcium levels.Another method involves testing compounds using an electrophysiologicalassay, such as patch clamping.

The term “alkanoyl” as used herein embraces an alkyl-C(O)— group whereinthe alkyl group is as defined herein. Examples of alkanoyl groupsinclude, but are not limited to, acetyl and propanoyl.

The term “alkyl,” either alone or within other terms such as “haloalkyl”and “alkylamino,” embraces linear or branched radicals having one toabout twelve carbon atoms. “Lower alkyl” radicals have one to about sixcarbon atoms. Examples of such radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl,hexyl and the like. The term “alkylene” embraces bridging divalentlinear and branched alkyl radicals. Examples include methylene,ethylene, propylene, isopropylene and the like.

The term “alkenyl” embraces linear or branched radicals having at leastone carbon-carbon double bond of two to about twelve carbon atoms.“Lower alkenyl” embraces radicals having two to about six carbon atoms.Examples of alkenyl radicals include ethenyl, propenyl, allyl, propenyl,butenyl and 4-methylbutenyl. The terms “alkenyl” and “lower alkenyl,”embrace radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations.

The term “alkoxy” as used herein contemplates an oxygen with a loweralkyl group as a substituent and includes methoxy, ethoxy, butoxy, andthe like.

The term “alkynyl” denotes linear or branched radicals having at leastone carbon-carbon triple bond and having two to about twelve carbonatoms. “Lower alkynyl” radicals have two to about six carbon atoms.Examples of such radicals include propargyl, butynyl, and the like.

The term “aroyl” as used herein embraces an aryl-CO— group wherein arylis as defined herein. Examples include, but are not limited to, benzoyl,naphth-1-oyl and naphth-2-oyl.

The term “aryl”, alone or in combination, means a carbocyclic aromaticsystem containing one or two rings wherein such rings may be attachedtogether in a fused manner. The term “aryl” embraces aromatic radicalssuch as phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl.

The term “comprising” is meant to be open ended, including the indicatedcomponent, but not excluding other elements.

“Conservatively modified variants” embrace both amino acid and nucleicacid sequences. With respect to particular nucleic acid sequences,conservatively modified variants refers to those nucleic acids whichencode identical or essentially identical amino acid sequences, or wherethe nucleic acid does not encode an amino acid sequence, to essentiallyidentical sequences. Because of the degeneracy of the genetic code, alarge number of functionally identical nucleic acids encode any givenprotein. For instance, the codons GCA, GCC, GCG and GCU all encode theamino acid alanine. Thus, at every position where an alanine isspecified by a codon, the codon can be altered to any of thecorresponding codons described without altering the encoded polypeptide.Such nucleic acid variations are “silent variations,” which are onespecies of conservatively modified variations. Every nucleic acidsequence herein which encodes a polypeptide also describes everypossible silent variation of the nucleic acid. One of skill willrecognize that each codon in a nucleic acid (except AUG, which isordinarily the only codon for methionine) can be modified to yield afunctionally identical molecule. Accordingly, each silent variation of anucleic acid which encodes a polypeptide is implicit in each describedsequence.

As to amino acid sequences, one of skill will recognize that individualsubstitutions, in a nucleic acid, peptide, polypeptide, or proteinsequence which alters a single amino acid or a small percentage of aminoacids in the encoded sequence is a “conservatively modified variant”where the alteration results in the substitution of an amino acid with achemically similar amino acid. Conservative substitution tablesproviding functionally similar amino acids are well known in the art.

The following six groups each contain amino acids that are conservativesubstitutions for one another:

1) Alanine (A), Serine (S), Threonine (T);

2) Aspartic acid (D), Glutamic acid (E);

3) Asparagine (N), Glutamine (Q);

4) Arginine (R), Lysine (K);

5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); and

6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W).

(see, e.g., Creighton, Proteins (1984)).

The term “cyclic group” means a cycloalkyl, heterocyclyl, aryl, orheteroaryl.

The term “cycloalkyl” includes saturated carbocyclic groups of 3 to 10carbons. Lower cycloalkyl groups include C₃-C₆ rings. Examples includecyclopentyl, cyclopropyl, and cyclohexyl.

As used herein, “cycloalkylalkyl” embraces an alkyl group wherein thealkyl group includes one or more cycloalkyl substituents (typicallyone). Examples include, but are not limited to, cyclohexylmethyl,cyclopentylmethyl, and cyclopropylmethyl.

The term “geminal” embraces two or more substituents that are directlyattached to the same atom. An example is 3,3-dimethyl substitution on acyclohexyl or spirocyclohexyl ring.

The term “halo” means halogens such as fluorine, chlorine, bromine oriodine atoms (i.e., fluoro, chloro, bromo, or iodo).

The term “haloalkyl” embraces radicals wherein any one or more of thealkyl carbon atoms is substituted with one or more halo as definedabove. Examples include monohaloalkyl, dihaloalkyl and polyhaloalkylradicals including perhaloalkyl. A monohaloalkyl radical, for oneexample, may have an iodo, bromo, chloro or fluoro atom within theradical. Dihalo and polyhaloalkyl radicals may have two or more of thesame halo atoms or a combination of different halo radicals. “Lowerhaloalkyl” embraces radicals having 1-6 carbon atoms. Examples ofhaloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. “Perfluoroalkyl” means an alkyl radical having allhydrogen atoms replaced with fluoro atoms. Examples includetrifluoromethyl and pentafluoroethyl.

The term “haloalkoxy” means alkoxy radicals wherein any one or more ofthe alkyl carbon atoms is substituted with one or more halo as definedabove. Examples include monohaloalkoxy, dihaloalkoxy and polyhaloalkoxyradicals including perhaloalkoxy. Examples further includedifluoromethoxy, trifluoromethoxy and trifluoroethoxy.

The term “heteroaryl” denotes aryl ring systems that contain one or moreheteroatoms selected from the group O, N and S, wherein the ringnitrogen and sulfur atom(s) are optionally oxidized, and nitrogenatom(s) are optionally quarternized. Examples include unsaturated 5 to 6membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, forexample, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl; unsaturated 5-to 6-membered heteromonocyclic group containing an oxygen atom, forexample, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-memberedheteromonocyclic group containing a sulfur atom, for example, 2-thienyl,3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example,oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5 to 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g.,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

The term “heteroaroyl” embraces a heteroaryl-C(O)— group whereinheteroaryl is as defined herein. Heteroaroyl groups include, but are notlimited to, thiophenyl, nicotinoyl, pyrrol-2-ylcarbonyl, and pyridinoyl.

The term “heterocyclyl” (or “heterocyclo”) embraces saturated, andpartially saturated, heteroatom-containing ring radicals, where theheteroatoms may be selected from nitrogen, sulfur and oxygen.Heterocyclic rings comprise monocyclic 6-8 membered rings, as well as5-16 membered bicyclic ring systems (which can include bridged fused andspiro-fused bicyclic ring systems). It does not include rings containing—O—O—, —O—S— or —S—S— portions.

Examples of saturated heterocyclo groups include saturated 3- to6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,piperazinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated heterocyclyl radicalsinclude dihydrothienyl, dihydropyranyl, dihydrofuryl, dihydrothiazolyl,and the like.

Particular examples of partially saturated and saturated heterocyclogroups include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl,indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl,isochromanyl, chromanyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl, and the like.

Heterocyclo groups also includes radicals where heterocyclic radicalsare fused/condensed with aryl radicals: unsaturated condensedheterocyclic group containing 1 to 5 nitrogen atoms, for example,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclic group containing1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl,benzoxadiazolyl]; unsaturated condensed heterocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl,benzothiadiazolyl]; and saturated, partially unsaturated and unsaturatedcondensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms[e.g. benzofuryl, benzothienyl, 2,3-dihydro-benzo[1,4]dioxinyl anddihydrobenzofuryl].

The term “heterocycloyl” embraces a heterocyclyl-C(O)— group whereinheterocyclyl is as defined herein. Examples include, but are not limitedto, N-methyl prolinoyl and tetrahydrofuranoyl.

The term “hydroxy” or “hydroxyl” embraces —OH.

The term “hydroxyalkyl” embraces radicals wherein any one or more of thealkyl carbon atoms is substituted with one or more hydroxy groups.Examples include hydroxymethyl, 2-hydroxyethyl, and (R)- or(S)-1-hydroxyethyl.

When any two substituent groups or any two instances of the samesubstituent group are “independently selected” from a list ofalternatives, the groups may be the same or different. For example, ifR^(a) and R^(b) are independently selected from alkyl, fluoro, amino,and hydroxyalkyl, then a molecule with two R^(a) groups and two R^(b)groups could have all groups be an alkyl group (e.g., four differentalkyl groups). Alternatively, the first R^(a) could be alkyl, the secondR^(a) could be fluoro, the first R^(b) could be hydroxyalkyl, and thesecond R^(b) could be amino (or any other substituents taken from thegroup). Alternatively, both R^(a) and the first R^(b) could be fluoro,while the second R^(b) could be alkyl (i.e., some pairs of substituentgroups may be the same, while other pairs may be different). In someembodiments, multiple instances of variables that may be selected from alist of alternatives are independently selected.

The term “interventional procedure” embraces any medical procedure usedfor diagnosis or treatment that involves incision, puncture, entry intoa body cavity, or the use of ionizing, electromagnetic or acousticenergy.

As used herein, “or” should in general be construed non-exclusively. Forexample, an embodiment of “a composition comprising A or B” wouldtypically present an aspect with a composition comprising both A and B,and an embodiment of “a method to treat or to prevent” could treat,prevent, or do a combination of both. “Or” should, however, be construedto exclude those aspects presented that cannot be combined withoutcontradiction (e.g., a composition pH that is between 9 and 10 orbetween 7 and 8).

The term “oxo” as used herein contemplates an oxygen atom attached witha double bond.

The term “periprocedurally” embraces administration of the compoundduring (intraprocedurally), before (preprocedurally), or after anmedical procedure (postprocedurally). In one embodiment, a compound ofthe present invention is administered (i) preprocedurally orpostprocedurally; and (ii) intraprocedurally. The compounds of thepresent invention are administered to a surgical, diagnostic, ortherapeutic procedure site by techniques well known to those of ordinaryskill in the art. The compound may be administered periprocedurally,which may include perioperatively (i.e., before, during or after asurgical procedure).

“Pharmaceutically acceptable” means approved or approvable by aregulatory agency of the Federal or state government or listed in theU.S. Pharmacopoeia or other generally recognized pharmacopoeia for usein animals, and more particularly in humans. It can be material which isnot biologically or otherwise undesirable, i.e., the material can beadministered to an individual without causing any undesirable biologicaleffects or interacting in a deleterious manner with any of thecomponents of the composition in which it is contained.

The term “pharmaceutically acceptable salt” of a compound means a saltthat is pharmaceutically acceptable (i.e., non-toxic at the therapeuticdosage) and that possesses the desired pharmacological activity of theparent compound. Such salts include, for example, acid addition saltsand base addition salts. Examples of pharmaceutically acceptable saltsinclude inorganic acid addition salts, such as chloride, bromide,sulfate, phosphate, and nitrate; organic acid addition salts, such asacetate, galactarate, propionate, succinate, lactate, glycolate, malate,tartrate, citrate, maleate, fumarate, methanesulfonate,p-toluenesulfonate, and ascorbate; salts with acidic amino acid, such asaspartate and glutamate; alkali metal salts, such as sodium salt andpotassium salt; alkaline earth metal salts, such as magnesium salt andcalcium salt; ammonium salt; organic base salts, such as trimethylaminesalt, triethylamine salt, pyridine salt, picoline salt,dicyclohexylamine salt, and N,N′-dibenzylethylenediamine salt; and saltswith a basic amino acid, such as lysine salt and arginine salt. Thesalts may be in some cases hydrates or ethanol solvates.

As used herein, a reference to a composition of formula A, B, C, or asalt thereof embraces A, a salt of A, B, a salt of B, C, or a salt of C.

The term “spirocycloalkyl” embraces a cycloalkyl in which geminalsubstituents on a carbon atom are replaced to join in forming a1,1-substituted ring. For example, but without limitation, for a—C(R¹)(R²)— group that was part of a longer carbon chain, if R¹ and R²joined to form a cyclopropyl ring incorporating the carbon to which R¹and R² were bonded, this would be a spirocycloalkyl group (i.e.,spirocyclopropyl).

The term “spiroheterocyclyl” embraces a heterocycloalkyl in whichgeminal substituents on a carbon atom are replaced to join in forming a1,1-substituted ring. For example, but without limitation, for a—C(R¹)(R²)— group that was part of a longer carbon chain, if R¹ and R²joined to form a pyrrolidine ring incorporating the carbon to which R¹and R² were bonded, this would be a spiroheterocyclyl group.

The term “TRPA1 modulator” is a composition that measurably increases ordecreases the activity of TRPA1.

Compounds of the present disclosure can exist as stereoisomers, whereinasymmetric or chiral centers are present. Stereoisomers are designated(R) or (S) depending on the configuration of substituents around thechiral carbon atom. The terms (R) and (S) used herein are configurationsas defined in IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem., (1976), 45: 13-30, herebyincorporated by reference. The present disclosure contemplates variousstereoisomers and mixtures thereof, and these isomers (e.g., asubstantially pure (R) or (S) enantiomer of a chiral compound of thepresent invention) are specifically included within the scope of thepresent disclosure. Stereoisomers include enantiomers, diastereomers,and mixtures of enantiomers or diastereomers. Individual stereoisomersof compounds of the present disclosure can be prepared syntheticallyfrom commercially available starting materials which contain asymmetricor chiral centers or by preparation of racemic mixtures followed byresolution well-known to those of ordinary skill in the art. Thesemethods of resolution are exemplified by (1) attachment of a mixture ofenantiomers to a chiral auxiliary, separation of the resulting mixtureof diastereomers by recrystallization or chromatography and liberationof the optically pure product from the auxiliary or (2) directseparation of the mixture of optical enantiomers on chiralchromatographic columns.

In some embodiments, the compounds of the invention can be obtained asN-oxides. Conversion of a tertiary amine group (i.e., a compound havingthe formula R₃N) in a compound of the invention to the correspondingN-oxide (i.e., a compound having the formula R₃N^(⊕)—O^(⊖)) can beconducted chemically according to methods that are known in the art.Conversion of a compound to the N-oxide can also occur afteradministration to a subject or patient. In certain cases, suchconversion is catalyzed enzymatically (e.g., by a cytochrome P450enzyme). In some instances, the N-oxide can be a metabolite of atertiary amine present in a compound of the invention. The N-oxide canbe an intermediate between the tertiary amine and its N-dealkylatedanalogs. Depending on the particular compound, an N-oxide can be moreactive or less active than its parent amine.

Where compounds of the present disclosure include F, I, C or H, thedisclosure is not limited to the most common isotopes of these elements.Compounds containing for example ¹⁸F, ¹⁹F, ¹¹C, ¹³C, ¹⁴C, ¹²³I, ¹²⁵I, ³Hand ²H are specifically contemplated as being included in thedisclosure. A compound of the invention can be radiolabeled according toa number of known techniques. A compound can be radiolabeled, forexample, by appending one or more radioisotopes of a halogen (e.g.,¹²⁵I) to an aromatic ring, or by alkylating a nitrogen of a compound ofthe invention with a group comprising a radioisotope. Radiolabeledcompounds can be used to measure binding of the compounds to TRPA1; todetect the compounds in cells, tissues, or organs of a subject to whomthe compounds are administered; to enable analysis of compoundmetabolism; or for radiotherapeutic techniques. Radiolabeled compoundsof the invention can also be used as competitive binders in studies forcharacterizing natural TRPA1 ligands. Isotopes of still other elementscan be used in conjunction with the compounds and methods of theinvention.

In the Summary of the Invention above, Detailed Description, and theclaims below, reference is made to particular features and aspects ofthe invention, including method steps. The disclosure of the inventionin this specification includes all possible combinations of suchparticular features within the embodiments of the invention disclosed,at least to the extent that such combinations are non-contradictory. Forexample, if the Detailed Description presents aspects A, B, and C of anembodiment, it is understood that this also discloses particularembodiments including both aspects A and B, both aspects B and C, andboth aspects A and C, as well as an embodiment with aspects A, B, and C.

II. Compounds of the Invention

In one aspect, the invention sets forth a compound of Formula I:

-   -   or a pharmaceutically acceptable salt thereof,        wherein:    -   A is a cyclic group of Formula Ia:

-   -   -   wherein Z¹, Z², Z³, Z⁴, and Z⁵ are each a member selected            from the group consisting of N, CH, and CR^(a); or,            alternatively for Z¹, the member Z¹ and X, together with            atoms in the rings to which they are attached, form an            additional fused, five- to eight-membered cycloalkyl or            heterocyclyl ring with from 0 to 4 R^(z) substituents;        -   with the proviso that at least one member selected from the            group consisting of Z², Z³, and Z⁴ is N;

    -   each R^(z) is a member independently selected from the group        consisting of halo, C₁-C₃ alkyl, C₁-C₃ haloalkyl, and C₁-C₃        alkoxy; or, alternatively, two R^(z) substituents, together with        the carbon atom to which they are attached, join to form an oxo,        spirocycloalkyl, or spiroheterocyclyl group;

    -   B is a cyclic group of Formula Ib:

-   -   -   wherein Y¹, Y², Y³, Y⁴, and Y⁵ are each a member            independently selected from the group consisting of N, CH,            and CR^(b); or, alternatively, the members —Y²═Y³— or            —Y⁴═Y⁵— are combined into a single member selected from the            group consisting of NR^(c), O, and S;

    -   each R^(a) and R^(b) is a member independently selected from the        group consisting of cyano, carboxyl, C₁-C₄ alkyl, C₃-C₈        cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,        halo, C₀-C₆ amino, C₁-C₆ amido, C₁-C₄ alkyloxycarbonyl, C₁-C₆        alkylsulfonyl, and hydroxyl; or, alternatively, two adjacent        R^(a) or R^(b), together with the atoms in groups A or B to        which they are attached, form an additional fused aryl,        heteroaryl, cycloalkyl, or heterocyclyl ring with from 0 to 4        R^(z) substituents;

    -   each R^(c) is a member independently selected from the group        consisting of hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆        cycloalkyl, (C₃-C₆ cycloalkyl)C₁-C₃alkyl, and C₁-C₇ acyl;

    -   each u is an integer independently selected from 0 to 4;

    -   v is an integer from 0 to 5;

    -   X is N or CR^(d); or, alternatively, X is CR^(d), wherein X and        the member Z¹, together with atoms in the rings in which they        are included, form the additional fused, five- to eight-membered        cycloalkyl or heterocyclyl ring with from 0 to 4 R^(z)        substituents;

    -   each R^(d) is a member independently selected from the group        consisting of halo, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄        alkoxy, C₁-C₄ haloalkoxy, C₃-C₆ cycloalkyl, and C₃-C₆        cycloalkoxy;

    -   each L¹, L², and L³, if present, is a member independently        selected from the group consisting of C═O, C═S, and C═NR^(c);

    -   C is a cyclic group of Formula Ic:

-   -   -   wherein Q is a member selected from the group consisting of            C(R^(e))(D), N(E), F, and G; or, alternatively, the members            —W³-Q- or —W⁴-Q- join to form a member H; and        -   wherein W¹, W², W³, and W⁴ are each an independently            selected C(R^(f))₂; or, alternatively, the members —W³-Q- or            —W⁴-Q- join to form a member H;

    -   R^(e) is a member selected from the group consisting of        hydrogen, C₁-C₃ alkyl, and C₁-C₃ fluoroalkyl; or, alternatively,        R^(e) and an R^(f) substituent of W¹, W², W³, or W⁴ join to form        a —(C(R^(z))₂)_(t)— bridge, wherein t is an integer selected        from 2 or 3;

    -   each R^(f) is a member independently selected from the group        consisting of hydrogen, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, and        halo; or, alternatively, two adjacent R^(f), together with the        atoms in group C to which they are attached, form an additional        aryl, heteroaryl, cycloalkyl, or heterocyclyl fused ring with        from 0 to 4 R^(z) substituents; or, alternatively, two geminal        R^(f), together with the atom in group C to which they are        attached, form a spirocycloalkyl or spiroheterocyclyl ring with        from 0 to 4 R^(z) substituents; or, alternatively, two axial        R^(f) substituents of a pair of W^(n) selected from the group        consisting of (W¹ and W²), (W² and W³), and (W³ and W⁴) join to        form a —(C(R^(z))₂)_(t)— bridge; or, alternatively, R^(e) and an        R^(f) substituent of W¹, W², W³, or W⁴ join to form a        —(C(R^(z))₂)_(t)— bridge;

    -   each t is an integer selected from 2 or 3;

    -   D is a bicyclic group of Formula Id:

-   -   E is a bicyclic group of Formula Ie:

-   -   F is a spirocyclic group of Formula If:

-   -   G is a bicyclic spirocyclic group of Formula Ig:

-   -   H is a fused group of Formula Ih:

-   -   -   wherein the H ring is a fused, five- to eight-membered            cycloalkyl or heterocyclyl ring;        -   wherein v is an integer from 0 to 4; and        -   wherein w is an integer from 0 to 2; and            Y⁶, Y⁷, Y⁸, Y⁹, and Y¹⁰, if present, are each a member            independently selected from the group consisting of N, CH,            and CR^(b); or, alternatively for Y⁸ and Y⁹, the members            —Y⁶═Y⁷— or —Y⁸═Y⁹— are combined into a single member            selected from the group consisting of NR^(c), O, and S.

In some embodiments, Q is C(R^(e))(D). In some embodiments, Q is N(E).In some embodiments, Q is F. In some embodiments, Q is G. In someembodiments, the members —W³-Q- or —W⁴-Q- join to form a member H.

In some embodiments, W¹, W², W³, and W⁴ comprise from 1 to 4independently selected R^(f) groups other than hydrogen. In someembodiments, W¹, W², W³, and W⁴ comprise from 1 to 4 independentlyselected R^(f) alkyl groups.

In some embodiments, W¹ and W² are combined into a single moiety W2(e.g., to form a pyrrolidine-based five-membered C ring rather than apiperidine- or piperazine-based six-membered C ring).

In some embodiments, C is a member selected from the group consistingof:

In some embodiments, C is a member selected from the group consistingof:

In some embodiments, the pair of W^(n) is selected from the groupconsisting of (W¹ and W²) and (W³ and W⁴). In some embodiments, C is amember selected from the group consisting of:

In some embodiments, D is a member selected from the group consistingof:

In some embodiments, D is a member selected from the group consistingof:

In some embodiments, D is a member selected from the group consistingof:

In some embodiments, D is a member selected from the group consistingof:

In some embodiments, L¹ is C═O. In some embodiments, L² is C═O. In someembodiments, L³ is C═O.

In some embodiments, the compound is selected from the group consistingof the compounds listed in Table 7. In some embodiments, the compound isselected from the group consisting of the compounds listed in Table 7 ashaving “A”-level activity. In some embodiments, the compound is selectedfrom compound 49, 55, 77, 99, 175, and 177.

In some embodiments, the compound is selected from the group consistingof1-(4-fluoro-3,5-dimethylphenyl)-8-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}-1,3,8-triazaspiro[4.5]decan-4-one;6,7-difluoro-1-(1-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}piperidin-4-yl)-2,3-dihydro-1H-1,3-benzodiazol-2-one;1′-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}-6-(trifluoromethyl)-1,2-dihydrospiro[3,1-benzoxazine-4,4′-piperidine]-2-one;1′-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}-6-(trifluoromethyl)-1,2-dihydrospiro[3,1-benzoxazine-4,4′-piperidine]-2-one;1′-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}-6-(trifluoromethyl)-1,2-dihydrospiro[3,1-benzoxazine-4,4′-piperidine]-2-one;1′-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}-6-(trifluoromethyl)-1,2-dihydrospiro[3,1-benzoxazine-4,4′-piperidine]-2-one;1′-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}-6-(trifluoromethyl)-1,2-dihydrospiro[3,1-benzoxazine-4,4′-piperidine]-2-one;2-fluoro-4-{3-[1-(4-fluoro-3,5-dimethylphenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carbonyl]-5-(pyridin-3-yl)-1H-pyrazol-1-yl}benzonitrile;8-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}-1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one;3-(1-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}piperidin-4-yl)-2-oxo-2,3-dihydro-1H-1,3-benzodiazole-5-carbonitrile;6,7-difluoro-1-(1-{1-[4-iodo-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}piperidin-4-yl)-2,3-dihydro-1H-1,3-benzodiazol-2-one;6,7-difluoro-1-(1-{1-[4-iodo-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}piperidin-4-yl)-2,3-dihydro-1H-1,3-benzodiazol-2-one;8-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}-3′-(4-fluorophenyl)-8-azaspiro[bicyclo[3.2.1]octane-3,4′-imidazolidine]-5′-one;6,7-difluoro-1-(1-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-1H,4H,5H-pyrido[2,3-g]indazole-3-carbonyl}piperidin-4-yl)-2,3-dihydro-1H-1,3-benzodiazol-2-one;5,6,7-trifluoro-1-(1-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}piperidin-4-yl)-2,3-dihydro-1H-1,3-benzodiazole-2-thione;6,7-difluoro-1-(1-{1-[4-fluoro-3-methyl-5-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}piperidin-4-yl)-2,3-dihydro-1H-1,3-benzodiazol-2-one;6-fluoro-2-oxo-1-{1-[5-(pyridin-3-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carbonyl]piperidin-4-yl}-2,3-dihydro-1H-1,3-benzodiazole-5-carbonitrile;1-{1-[5-(6-chloropyridin-3-yl)-1-[3-fluoro-4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carbonyl]piperidin-4-yl}-6,7-difluoro-2,3-dihydro-1H-1,3-benzodiazol-2-one;6,7-difluoro-1′-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}-1,2-dihydrospiro[3,1-benzoxazine-4,4′-piperidine]-2-one;6,7-difluoro-1-{1-[1-(4-iodophenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl]piperidin-4-yl}-2,3-dihydro-1H-1,3-benzodiazol-2-one;1-(4-fluorophenyl)-8-[1-(4-iodophenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl]-1,3,8-triazaspiro[4.5]decan-4-one;6,7-difluoro-1-(1-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-1H,4H,5H-pyrido[3,2-g]indazole-3-carbonyl}piperidin-4-yl)-2,3-dihydro-1H-1,3-benzodiazol-2-one;1-{1-[5-(2-chloropyridin-3-yl)-1-[3-fluoro-4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carbonyl]piperidin-4-yl}-6,7-difluoro-2,3-dihydro-1H-1,3-benzodiazol-2-one;6,7-difluoro-1-{8-[5-(pyridin-3-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carbonyl]-8-azabicyclo[3.2.1]octan-3-yl}-2,3-dihydro-1H-1,3-benzodiazol-2-one;1-(4-fluorophenyl)-8-{1-[4-iodo-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}-1,3,8-triazaspiro[4.5]decan-4-one;5,6,7-trifluoro-1-(1-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}piperidin-4-yl)-2,3-dihydro-1H-1,3-benzodiazol-2-one;8-[5-(6-chloropyridin-3-yl)-1-[3-fluoro-4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carbonyl]-1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one;6,7-difluoro-1-(1-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}piperidin-4-yl)-2,3-dihydro-1H-1,3-benzodiazole-2-thione;1-(1-{1-[3,4-bis(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}piperidin-4-yl)-6,7-difluoro-2,3-dihydro-1H-1,3-benzodiazol-2-one;1-{1-[4-bromo-5-(pyridin-3-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carbonyl]piperidin-4-yl}-6,7-difluoro-2,3-dihydro-1H-1,3-benzodiazol-2-one;(8aS)-7-{1-[3-fluoro-4-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}-hexahydro-1H-[1,3]oxazolo[3,4-a]piperazin-3-one;2-fluoro-5-{3-[1-(4-fluoro-3,5-dimethylphenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carbonyl]-5-(pyridin-3-yl)-1H-pyrazol-1-yl}benzonitrile;5,6-difluoro-1′-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}-1,2-dihydrospiro[3,1-benzoxazine-4,4′-piperidine]-2-one;8-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-5-(pyrazin-2-yl)-1H-pyrazole-3-carbonyl}-1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one;6,7-difluoro-1-(1-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-5-(pyrazin-2-yl)-1H-pyrazole-3-carbonyl}piperidin-4-yl)-2,3-dihydro-1H-1,3-benzodiazol-2-one;8-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-1H,4H,5H-pyrido[2,3-g]indazole-3-carbonyl}-1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one;1-(3,5-dichloro-4-fluorophenyl)-8-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}-1,3,8-triazaspiro[4.5]decan-4-one;8-{1-[3-fluoro-4-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}-3′-(4-fluorophenyl)-8-azaspiro[bicyclo[3.2.1]octane-3,4′-imidazolidine]-5′-one;6-fluoro-1-(1-{1-[3-fluoro-4-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}piperidin-4-yl)-7-(trifluoromethyl)-2,3-dihydro-1H-1,3-benzodiazol-2-one;8-{1-[4-chloro-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}-1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one;5-{3-[4-(6,7-difluoro-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-1-carbonyl]-5-(pyridin-3-yl)-1H-pyrazol-1-yl}-2-fluorobenzonitrile;4-{3-[1-(3,4-difluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decane-8-carbonyl]-5-(pyridin-3-yl)-1H-pyrazol-1-yl}-2-fluorobenzonitrile;1-(4-fluoro-3,5-dimethylphenyl)-8-{1-[3-fluoro-4-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}-1,3,8-triazaspiro[4.5]decan-4-one;4-{3-[4-(6,7-difluoro-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-1-carbonyl]-5-(pyridin-3-yl)-1H-pyrazol-1-yl}-2-(trifluoromethyl)benzonitrile;5-fluoro-3-(1-{1-[3-fluoro-4-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}piperidin-4-yl)-2-oxo-2,3-dihydro-1H-1,3-benzodiazole-4-carbonitrile;6,7-difluoro-1-(1-{1-[2-methyl-4-(trifluoromethoxy)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}piperidin-4-yl)-2,3-dihydro-1H-1,3-benzodiazol-2-one;1-(1-{1-[2,5-difluoro-4-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}piperidin-4-yl)-6,7-difluoro-2,3-dihydro-1H-1,3-benzodiazol-2-one;1-(1-{1-[3-fluoro-4-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}piperidin-4-yl)-2-oxo-2,3-dihydro-1H-1,3-benzodiazole-5-carbonitrile;1-(1-{1-[4-chloro-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}piperidin-4-yl)-6,7-difluoro-2,3-dihydro-1H-1,3-benzodiazol-2-one;6-fluoro-1-(1-{1-[3-fluoro-4-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}piperidin-4-yl)-2-oxo-2,3-dihydro-1H-1,3-benzodiazole-5-carbonitrile;1-(4-fluoro-3,5-dimethylphenyl)-8-[5-(pyridin-3-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carbonyl]-1,3,8-triazaspiro[4.5]decan-4-one;6-fluoro-1′-{1-[3-fluoro-4-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}-1,2-dihydrospiro[3,1-benzoxazine-4,4′-piperidine]-2-one;4-{3-[4-(6,7-difluoro-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-1-carbonyl]-5-(pyridin-3-yl)-1H-pyrazol-1-yl}-2-fluorobenzonitrile;6,7-difluoro-1-(1-{1-[3-fluoro-4-(trifluoromethyl)phenyl]-5-(4-methylpyridin-3-yl)-1H-pyrazole-3-carbonyl}piperidin-4-yl)-2,3-dihydro-1H-1,3-benzodiazol-2-one;5-fluoro-2-oxo-3-{1-[5-(pyridin-3-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carbonyl]piperidin-4-yl}-2,3-dihydro-1H-1,3-benzodiazole-4-carbonitrile;1-(1-{1-[2,3-difluoro-4-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}piperidin-4-yl)-6,7-difluoro-2,3-dihydro-1H-1,3-benzodiazol-2-one;2-fluoro-4-(3-{[3′-(4-fluorophenyl)-5′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,4′-imidazolidine]-8-yl]carbonyl}-5-(pyridin-3-yl)-1H-pyrazol-1-yl)benzonitrile;8-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-1H,4H,5H-pyrido[3,2-g]indazole-3-carbonyl}-1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one;6-fluoro-1′-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}-1,2-dihydrospiro[3,1-benzoxazine-4,4′-piperidine]-2-one;6,7-difluoro-1-(1-{1-[3-fluoro-4-(trifluoromethyl)phenyl]-5-(5-fluoropyridin-3-yl)-1H-pyrazole-3-carbonyl}piperidin-4-yl)-2,3-dihydro-1H-1,3-benzodiazol-2-one;6,7-difluoro-1-(8-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}-8-azabicyclo[3.2.1]octan-3-yl)-2,3-dihydro-1H-1,3-benzodiazol-2-one;6,7-difluoro-1-(1-{1-[3-fluoro-4-(trifluoromethyl)phenyl]-5-(pyridazin-4-yl)-1H-pyrazole-3-carbonyl}piperidin-4-yl)-2,3-dihydro-1H-1,3-benzodiazol-2-one;6-chloro-1′-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}-1,2-dihydrospiro[3,1-benzoxazine-4,4′-piperidine]-2-one;6,7-difluoro-1-{1-[5-(pyridazin-4-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carbonyl]piperidin-4-yl}-2,3-dihydro-1H-1,3-benzodiazol-2-one;6,7-difluoro-1-(1-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}-2-methylpiperidin-4-yl)-2,3-dihydro-1H-1,3-benzodiazol-2-one;7-fluoro-1′-{1-[4-fluoro-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}-1,2-dihydrospiro[3,1-benzoxazine-4,4′-piperidine]-2-one;1-(1-{1-[2,4-difluoro-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}piperidin-4-yl)-6,7-difluoro-2,3-dihydro-1H-1,3-benzodiazol-2-one;8-{1-[2,4-difluoro-3-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl}-1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one;1-{1-[5-(1-benzyl-1H-imidazol-4-yl)-1-[4-fluoro-3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carbonyl]piperidin-4-yl}-6,7-difluoro-2,3-dihydro-1H-1,3-benzodiazol-2-one;and8-[5-(1-benzyl-1H-imidazol-4-yl)-1-[4-fluoro-3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carbonyl]-1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one.

In some embodiments, Z¹, Z², Z³, Z⁴, and Z⁵ are each a member selectedfrom the group consisting of N, CH, and CR^(a).

In some embodiments, Z¹ and X, together with atoms in the rings to whichthey are attached, form an additional fused, five- to eight-memberedcycloalkyl or heterocyclyl ring with from 0 to 4 R^(z) substituents.

In some embodiments, Z² is N. In some preferred embodiments, Z³ or Z⁴ isN. In some embodiments, Z³ is N. In some embodiments, Z⁴ is N.

In some embodiments, A is a member selected from the group consistingof:

and salts thereof.

In some embodiments, A is a member selected from the group consistingof:

and salts thereof.

In some embodiments, A is a member selected from the group consistingof:

and salts thereof.

In some embodiments, A is a member selected from the group consistingof:

and salts thereof.

In some embodiments, Y¹, Y², Y³, Y⁴, and Y⁵ are each a memberindependently selected from the group consisting of N, CH, and CR^(b).

In some embodiments, Y¹ is N. In some embodiments, Y¹ is CH.

In some embodiments, Y¹ is CR^(b). In some embodiments, the Y¹ R^(b) isa member selected from the group consisting of chloro, cyano, fluoro,methyl, trifluoromethyl, and trifluoromethoxy.

In some embodiments, Y² is N. In some embodiments, Y² is CH.

In some embodiments, Y² is CR^(b). In some embodiments, the Y² R^(b) isa member selected from the group consisting of chloro, cyano, fluoro,methyl, trifluoromethyl, and trifluoromethoxy.

In some embodiments, Y³ is N. In some embodiments, Y³ is CH.

In some embodiments, Y³ is CR^(b). In some embodiments, the Y³ R^(b) isa member selected from the group consisting of chloro, cyano, fluoro,methyl, trifluoromethyl, and trifluoromethoxy.

In some embodiments, Y⁴ is N. In some embodiments, Y⁴ is CH.

In some embodiments, Y⁴ is CR^(b). In some embodiments, the Y⁴ R^(b) isa member selected from the group consisting of chloro, cyano, fluoro,methyl, trifluoromethyl, and trifluoromethoxy.

In some embodiments, Y⁵ is N. In some embodiments, Y⁵ is CH.

In some embodiments, Y⁵ is CR^(b). In some embodiments, the Y⁵ R^(b) isa member selected from the group consisting of chloro, cyano, fluoro,methyl, trifluoromethyl, and trifluoromethoxy.

In some embodiments, B is a member selected from the group consistingof:

In some embodiments, B is a member selected from the group consistingof:

In some embodiments, B is a member selected from the group consistingof:

In some embodiments, B is a member selected from the group consistingof:

In some embodiments, each R^(a) and R^(b) is a member independentlyselected from the group consisting of cyano, C₁-C₄ alkyl, C₁-C₄ alkoxy,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, halo, C₀-C₆ amino, C₁-C₆ amido, andhydroxyl. In some embodiments, each R^(a) and R^(b) is a memberindependently selected from the group consisting of cyano, C₁-C₄ alkyl,C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, and halo.

In some embodiments, u is an integer independently selected from 0 to 3(e.g., 0, 1, 2, or 3). In some embodiments, u is an integerindependently selected from 0 to 4 (e.g., 0, 1, 2, 3, or 4). In someembodiments, u is an integer independently selected from 0 to 5 (e.g.,0, 1, 2, 3, 4, or 5).

In some embodiments, v is an integer independently selected from 0 to 3(e.g., 0, 1, 2, or 3). In some embodiments, v is an integerindependently selected from 0 to 4 (e.g., 0, 1, 2, 3, or 4). In someembodiments, v is an integer independently selected from 0 to 5 (e.g.,0, 1, 2, 3, 4, or 5).

In some embodiments, X is N.

In some embodiments, each R^(c) is independently selected from the groupconsisting of hydrogen, cyano, C₁-C₃ alkyl, trifluoromethyl, cycloalkyl,trifluoromethoxy, and C₁-C₃ alkoxy. In some embodiments, each R^(c) isindependently selected from the group consisting of hydrogen, cyano,C₁-C₃ alkyl, trifluoromethyl, cyclopropyl, trifluoromethoxy, and C₁-C₃alkoxy. In some embodiments, each R^(c) is independently selected fromthe group consisting of hydrogen, methyl, bromo, chloro,trifluoromethyl, ethyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl,and cyclopropylmethyl.

In some embodiments, Y⁶ is N. In some embodiments, Y⁶ is CH.

In some embodiments, Y⁶ is CR^(b). In some embodiments, the Y⁶ R^(b) isa member selected from the group consisting of chloro, cyano, fluoro,methyl, trifluoromethyl, and trifluoromethoxy. In some embodiments, theY⁶ R^(b) is a member selected from the group consisting of chloro,cyano, fluoro, methyl, trifluoromethyl, trifluoromethoxy, —C(O)N(H)Me,—NMe₂, and —SO₂Me.

In some embodiments, Y⁷ is N. In some embodiments, Y⁷ is CH.

In some embodiments, Y⁷ is CR^(b). In some embodiments, the Y⁷ R^(b) isa member selected from the group consisting of chloro, cyano, fluoro,methyl, trifluoromethyl, and trifluoromethoxy. In some embodiments, theY⁷ R^(b) is a member selected from the group consisting of chloro,cyano, fluoro, methyl, trifluoromethyl, trifluoromethoxy, —C(O)N(H)Me,—NMe₂, and —SO₂Me.

In some embodiments, Y⁸ is N. In some embodiments, Y⁸ is CH.

In some embodiments, Y⁸ is CR^(b). In some embodiments, the Y⁸ R^(b) isa member selected from the group consisting of chloro, cyano, fluoro,methyl, trifluoromethyl, and trifluoromethoxy. In some embodiments, theY⁸ R^(b) is a member selected from the group consisting of chloro,cyano, fluoro, methyl, trifluoromethyl, trifluoromethoxy, —C(O)N(H)Me,—NMe₂, and —SO₂Me.

In some embodiments, Y⁹ is N. In some embodiments, Y⁹ is CH.

In some embodiments, Y⁹ is CR^(b). In some embodiments, the Y⁹ R^(b) isa member selected from the group consisting of chloro, cyano, fluoro,methyl, trifluoromethyl, and trifluoromethoxy. In some embodiments, theY⁹ R^(b) is a member selected from the group consisting of chloro,cyano, fluoro, methyl, trifluoromethyl, trifluoromethoxy, —C(O)N(H)Me,—NMe₂, and —SO₂Me.

In some embodiments, Y¹⁰ is N. In some embodiments, Y¹⁰ is CH.

In some embodiments, Y¹⁰ is CR^(b). In some embodiments, the Y¹⁰ R^(b)is a member selected from the group consisting of chloro, cyano, fluoro,methyl, trifluoromethyl, and trifluoromethoxy. In some embodiments, theY¹⁰ R^(b) is a member selected from the group consisting of chloro,cyano, fluoro, methyl, trifluoromethyl, trifluoromethoxy, —C(O)N(H)Me,—NMe₂, and —SO₂Me.

In aspects or embodiments directed to Markush groups, in some furtherembodiments, the present invention is directed only to a single memberof the Markush group.

In some embodiments,

is a member selected from the group consisting of:

In some embodiments,

is a member selected from the group consisting of:

In aspects or embodiments directed to Markush groups, in some furtherembodiments, the present invention is directed only to a single memberof the Markush group.

In some embodiments, the compound is selected from the group consistingof:

In some embodiments, the compound is selected from the group consistingof:

In some embodiments, the compound is selected from the group consistingof:

In some embodiments, the compound is selected from the group consistingof:

In some embodiments, the compound is selected from the group consistingof:

In some embodiments, the compound is selected from the group consistingof:

In some embodiments, the compound is selected from the group consistingof:

In some embodiments, the compound is selected from the group consistingof:

In some embodiments, the compound is selected from the group consistingof:

In some embodiments, the compound incorporates the features of one ormore of the structural features of embodiments set forth for Formula IIor Formula III. In some embodiments, the compound combines the featuresof two (or more) embodiments.

In one aspect, the invention provides a compound of Formula II:

-   -   or a pharmaceutically acceptable salt thereof;        wherein:    -   A is a cyclic group of Formula IIa:

-   -   -   wherein Z¹, Z², Z³, Z⁴, and Z⁵ are each a member selected            from the group consisting of N, CH, and CR^(a); or,            alternatively for Z¹, the member Z¹ and X, together with            atoms in the rings to which they are attached, form an            additional fused, five- to eight-membered cycloalkyl or            heterocyclyl ring with from 0 to 5 R^(z) substituents;        -   with the proviso that at least one member selected from the            group consisting of Z², Z³, and Z⁴ is N;

    -   each R^(z) is a member independently selected from the group        consisting of halo, C₁-C₃ alkyl, C₁-C₃ haloalkyl, and C₁-C₃        alkoxy; or, alternatively, two R^(z) substituents, together with        the carbon atom to which they are attached, join to form an oxo,        spirocycloalkyl, or spiroheterocyclyl group;

    -   B is a cyclic group of Formula IIb:

-   -   -   wherein Y¹, Y², Y³, Y⁴, and Y⁵ are each a member            independently selected from the group consisting of N, CH,            and CR^(b); or, alternatively, the members —Y²═Y³— or            —Y⁴═Y⁵— are combined into a single member selected from the            group consisting of NH, NR^(c), O, and S;

    -   each R^(a) and R^(b) is a member independently selected from the        group consisting of cyano, carboxyl, C₁-C₄ alkyl, C₁-C₄        hydroxyalkyl, C₃-C₈ cycloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,        C₁-C₄ haloalkoxy, halo, C₀-C₆ amino, C₁-C₆ amido, C₁-C₄        alkyloxycarbonyl, C₁-C₆ alkylsulfonyl, and hydroxyl; or,        alternatively, two adjacent R^(a) or R^(b), together with the        atoms in groups A or B to which they are attached, form an        additional fused aryl, heteroaryl, cycloalkyl, or heterocyclyl        ring with from 0 to 5 R^(z) substituents;

    -   each R^(c) is a member independently selected from the group        consisting of hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆        cycloalkyl, (C₃-C₆ cycloalkyl)C₁-C₃alkyl, and C₁-C₇ acyl;

    -   each u is an integer independently selected from 0 to 4;

    -   v is an integer from 0 to 5;

    -   X is N or CR^(d); or, alternatively, X is CR^(d), wherein X and        the member Z¹, together with atoms in the rings in which they        are included, form the additional fused, five- to eight-membered        cycloalkyl or heterocyclyl ring with from 0 to 5 R^(z)        substituents;

    -   each R^(d) is a member independently selected from the group        consisting of halo, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄        alkoxy, C₁-C₄ haloalkoxy, C₃-C₆ cycloalkyl, and C₃-C₆        cycloalkoxy;

    -   L¹ is a member selected from the group consisting of C═O, C═S,        and C═NR^(c);

    -   Y⁶, Y⁷, Y⁸, Y⁹, and Y¹⁰, if present, are each a member        independently selected from the group consisting of N, CH, and        CR^(b); or, alternatively for Y⁸ and Y⁹, the members —Y⁶═Y⁷— or        —Y⁸═Y⁹— are combined into a single member selected from the        group consisting of NR^(c), O, and S.

In some embodiments, the compound incorporates the features of one ormore of the structural features of embodiments set forth for Formula Ior Formula III. In some embodiments, the compound combines the featuresof two (or more) embodiments.

In one aspect, the invention provides compounds according to Formula IIIor a pharmaceutically acceptable salt thereof:

or

wherein:

-   -   Ring A and Ring B are each independently:    -   a 5- or 6-membered cyclic group with the proviso that Ring A and        Ring B are not both unsubstituted phenyl; or    -   a 9-10-membered fused aromatic bicyclic ring with optionally 1,        2, 3, or 4 heteroatoms selected from N, O or S as part of the        9-10 members;    -   R^(a) and R^(b) are each independently selected from the group        consisting of —CN, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl,        C₁-C₄ haloalkoxy, halogen, and hydroxy;    -   optionally, two R^(a), together with the atoms in Ring A to        which they are attached, join to form a ring;    -   optionally, two R^(b), together with the atoms in Ring B to        which they are attached, join to form a ring;    -   u and v are each independently 0, 1, 2, or 3;    -   X is CR^(x) or N, wherein R^(x) is selected from H, —CN, C₁-C₃        alkyl, —CF₃ cyclopropyl, and C₁-C₃ alkoxy;    -   L is —[C(O)]_(0,1)—(CH₂)_(0,1,2)—    -   Ring C is option A, option B, or option C wherein:    -   option A is

or a fused 8-14 member bi- or tri-cyclic cyclic group optionally having1-4 heteroatoms selected from N and O and optionally substituted with1-4 R³ wherein:

-   -   Y is a bond, —CH₂—, —S(O)₂—, —S(O)—, —C(O)—, —NH—, or —O—; with        the proviso that if two Y are bonds, the third Y is —CH₂—;    -   each Z is independently —CH₂—, —NH—, —S—, or —O— with the        proviso that at least 2 of Z are —CH₂—;    -   each n is independently 0, 1 or 2 provided that if one n is 0,        the other n is not 0;    -   s is 0, 1, 2, 3, or 4;    -   t is 1, 2, 3, or 4;    -   each R^(1a) is independently C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄        haloalkoxy, C₁-C₄ haloalkyl, —CN, or halogen;    -   R^(1b) is:    -   an 8- to 9-membered bicyclic cyclic group having 0, 1, or 2        heteroatoms selected from S, N, and O, substituted by one or        more oxo or (═S) and optionally substituted by one or more        substituents selected from the group consisting of halogen,        C₁-C₄ alkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl, or    -   —R⁴-R⁵ wherein each of R⁴ and R⁵ are a 5- to 6-membered cyclic        group having 0, 1, or 2 heteroatoms selected from N and O and        each optionally substituted with oxo, halogen, C₁-C₄ alkyl,        C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl;    -   each R² is independently selected from the group consisting of        —CN, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, —(C₁-C₄        alkyl)-OH, C₁-C₄ haloalkyl, halogen, oxo, hydroxy, and 5- to        9-membered mono- or bicyclic cyclic group having 0, 1, or 2        heteroatoms selected from N and O, and wherein:    -   if one R² is oxo, t is 2 or 3 and one R² is other than oxo,    -   if R² is a cyclic group, it is optionally substituted by one or        more substituents selected from the group consisting of —CN,        halogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl, and    -   optionally, two R², together with the atoms to which they are        attached, join to form a 5- or 6-membered cyclic group        optionally substituted with 1-4 substituents selected from the        group consisting of —CN, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkoxy,        and C₁-C₄ haloalkyl;    -   one R³ is oxo and any remaining R³ is independently selected        from the group consisting of 5- to 9-membered mono- or bicyclic        cyclic group having 0, 1, or 2 heteroatoms selected from N and        O, —CN, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄        haloalkyl, halogen, oxo, and hydroxyl, and if R³ is a cyclic        group, it is optionally substituted by one or more substituents        selected from the group consisting of halogen, C₁-C₄ alkyl and        C₁-C₄ haloalkyl;    -   option B is if Ring A is a 6-membered cyclic group, Ring C is        selected from the group consisting of a fused 8-14 member bi- or        tri-cyclic cyclic group optionally having 1-4 heteroatoms        selected from N and O and optionally substituted by 1-3 R³,

wherein:

-   -   Y is a bond, —CH₂—, —S(O)₂—, —S(O)—, —C(O)—, —NH—, or —O— with        the proviso that if two Y are bonds, the third Y is —CH₂—;    -   each n is independently 0, 1 or 2 provided that if one n is 0,        the other n is not 0;    -   each Z is independently —CH₂—, —NH—, —S— or —O—, with the        proviso that at least 2 of Z are —CH₂—;    -   each R^(1a) is independently C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄        haloalkoxy, C₁-C₄ haloalkyl, —CN, or halogen;    -   R^(1b) is:    -   a 5- to 9-membered mono- or bicyclic cyclic group having 0, 1,        or 2 heteroatoms selected from S, N and O optionally substituted        by one or more substituents selected from the group consisting        of (═S), oxo, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkoxy and C₁-C₄        haloalkyl and wherein if Ring C is

each n is 1 and s is 0, then R^(1b) is not phenyl, pyridine, orpyrimidine, or

-   -   —R⁴-R⁵ wherein each of R⁴ and R⁵ are a 5- to 6-membered cyclic        group having 0, 1 or 2 heteroatoms selected from N and O and        each optionally substituted with oxo, halogen, C₁-C₄ alkyl,        C₁-C₄ haloalkoxy and C₁-C₄ haloalkyl;    -   each R² and R³ is independently selected from the group        consisting of 5- to 9-membered mono- or bicyclic cyclic group        having 0, 1 or 2 heteroatoms selected from N and O, —CN, C₁-C₄        alkyl, —(C₁-C₄ alkyl)-OH, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄        haloalkyl, halogen, oxo, and hydroxy and if R² is a cyclic        group, it is optionally substituted by one or more substituents        selected from the group consisting of —CN, halogen, C₁-C₄ alkyl,        and C₁-C₄ haloalkyl;    -   optionally, two R², together with the atoms to which they are        attached, join to form a 5- or 6-membered cyclic group        optionally substituted with 1-4 substituents selected from the        group consisting of —CN, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkoxy,        and C₁-C₄ haloalkyl;    -   s is 0, 1, 2, 3 or 4; and    -   t is 0, 1, 2, 3 or 4;    -   with the proviso that, in option B, if X is N, Ring C is not

or

-   -   option C is if Ring A is a 6-membered cyclic group other than        pyridine, Ring C is selected from the group consisting of a        fused 8-14 member bi- or tri-cyclic cyclic group optionally        having 1-4 heteroatoms selected from N and O and optionally        substituted by 1-3 R³,

wherein:

-   -   Y is a bond, —CH₂—, —S(O)₂—, —S(O)—, —C(O)—, —NH—, or —O— with        the proviso that if two Y are bonds, the third Y is —CH₂—;    -   each n is independently 0, 1 or 2 provided that if one n is 0,        the other n is not 0;    -   each Z is independently —CH₂—, —NH—, —S—, or —O— with the        proviso that at least 2 of Z are —CH₂—;    -   each R^(1a) is independently C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄        haloalkoxy, C₁-C₄ haloalkyl, —CN, or halogen;    -   R^(1b) is:        -   a 5- to 9-membered mono- or bicyclic cyclic group having 0,            1 or 2 heteroatoms selected from S, N and O optionally            substituted by one or more substituents selected from the            group consisting of (═S), oxo, halogen, C₁-C₄ alkyl, C₁-C₄            haloalkoxy, and C₁-C₄ haloalkyl, or        -   —R⁴-R⁵ wherein each of R⁴ and R⁵ are a 5- to 6-membered            cyclic group having 0, 1, or 2 heteroatoms selected from N            and O and each optionally substituted with oxo, halogen,            C₁-C₄ alkyl, C₁-C₄ haloalkoxy and C₁-C₄ haloalkyl;    -   each R² and R³ is independently selected from the group        consisting of 5- to 9-membered mono- or bicyclic cyclic group        having 0, 1 or 2 heteroatoms selected from N and O, —CN, —C₁-C₄        alkyl, —(C₁-C₄ alkyl)-OH, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄        haloalkyl, halogen, oxo and hydroxy and if R² is a cyclic group,        it is optionally substituted by one or more substituents        selected from the group consisting of —CN, halogen, C₁-C₄ alkyl        and C₁-C₄ haloalkyl;    -   optionally, two R², together with the atoms to which they are        attached, join to form a 5- or 6-membered cyclic group        optionally substituted with 1-4 substituents selected from the        group consisting of —CN, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkoxy,        and C₁-C₄ haloalkyl;    -   s is 0, 1, 2, 3, or 4; and    -   t is 0, 1, 2, 3, or 4;        with the proviso that, in option C, if X is N, Ring C is not

R^(N) is H or C₁-C₄ alkyl; andR^(c) is:

-   -   a 5-6 membered heteroaryl optionally substituted by 1-4 R⁴;    -   a fused 8-10 member cyclic group having 0, 1, or 2 heteroatoms        selected from N and O and optionally substituted by 1-3 R⁴ if        R^(N) is other than H; or    -   if Ring A is a 6-membered cyclic group, R^(c) is a fused 8-10        member cyclic group having 0, 1, or 2 heteroatoms selected from        N and O and optionally substituted by 1-3 R⁴ wherein:    -   each R⁴ is independently selected from the group consisting of        5- to 9-membered mono- or bicyclic cyclic group having 0, 1 or 2        heteroatoms selected from N and O, —CN, —C₁-C₄ alkyl, —(C₁-C₄        alkyl)-OH, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ haloalkyl,        halogen, oxo, and hydroxy; and    -   if R⁴ is a cyclic group, it is optionally substituted by one or        more substituents selected from the group consisting of —CN,        halogen, C₁-C₄ alkyl, and C₁-C₄ haloalkyl.

In some embodiments two R², together with the atoms to which they areattached, join to form a 5- or 6-membered aryl or heteroaryl groupoptionally substituted with 1-4 substituents selected from the groupconsisting of —CN, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkoxy, and C₁-C₄haloalkyl.

In some embodiments two R², together with the atoms to which they areattached, join to form a 5- or 6-membered aryl or heteroaryl groupoptionally substituted with 1-4 substituents selected from the groupconsisting of halogen, C₁-C₄ alkyl, C₁-C₄ haloalkoxy, and C₁-C₄haloalkyl.

In some embodiments at least one of Ring A or Ring B is an aryl orheteroaryl group.

In some embodiments at least one of Ring A or Ring B is a 6-memberedaryl or 6-membered heteroaryl group.

In some embodiments both of Ring A and Ring B are either a 6-memberedaryl or a 6-membered heteroaryl group.

In some embodiments both of Ring A and Ring B are not phenyl.

In some embodiments at least one of Ring A and Ring B is a 5-memberedcyclic group having two heteroatoms.

In some embodiments Ring A is a 6-membered cyclic group or a 5-memberedcyclic group wherein the 5-membered cyclic group includes 0, 2, or 3heteroatoms.

In some embodiments Ring B is a 6-membered cyclic group or a 5-memberedcyclic group wherein the 5-membered cyclic group includes 0, 2 or 3heteroatoms.

In some embodiments each R^(a) is independently —CN, halogen, a C₁-C₄haloalkoxy, a C₁-C₄ haloalkyl, or C₁-C₄ alkyl; independently halogen, aC₁-C₄ haloalkoxy, a C₁-C₄ haloalkyl or C₁-C₄ alkyl; independently —CN,F, Cl, —OCF₃, —OCHF₂, —CF₃ or —CH₃; or independently F, Cl, —OCF₃,—OCHF₂, —CF₃, or —CH₃.

In some embodiments u is 1, 2, or 3, and each R^(a) is independently For —CF₃.

In some embodiments each R^(b) is independently —CN, halogen, a C₁-C₄haloalkoxy, a C₁-C₄ haloalkyl, or C₁-C₄ alkyl; independently halogen, aC₁-C₄ haloalkoxy, a C₁-C₄ haloalkyl or C₁-C₄ alkyl; independently —CN,F, Cl, —OCF₃, —OCHF₂, —CF₃ or —CH₃; or independently F, Cl, —OCF₃,—OCHF₂, —CF₃, or —CH₃.

In some embodiments each R^(b) is independently —CN, halogen, a C₁-C₄haloalkoxy, a C₁-C₄ haloalkyl, or C₁-C₄ alkyl.

In some embodiments each R^(b) is independently —CN, F, Cl, —OCF₃,—OCHF₂, —CF₃, or —CH₃.

In some embodiments v is 1, 2 or 3 and each R^(b) is independently F or—CF₃.

In a first aspect Ring C is

In a second aspect Ring C is

In some embodiments of the first or second aspects Y is —CH₂—.

In some embodiments of the first or second aspects R^(1b) is a 5- to9-membered mono- or bicyclic cyclic group having 0, 1, 2, or 3heteroatoms selected from S, N and O and substituted by one or moresubstituents selected from the group consisting of oxo, halogen, C₁-C₄alkyl, C₁-C₄ haloalkoxy, and C₁-C₄ haloalkyl.

In some embodiments of the first or second aspects R^(1b) is

which is optionally substituted by one or more substituents selectedfrom the group consisting of (═S), oxo, halogen, C₁-C₄ alkyl, C₁-C₄haloalkoxy and C₁-C₄ haloalkyl and wherein each Q is independentlyselected from —N—, —NH—, —CH— and —CH₂— provided that nor more thanthree Q are —N— or —NH—. In some embodiments of the first or secondaspects R^(1b) is

which is optionally substituted by one or more substituents selectedfrom the group consisting of oxo, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkoxyand C₁-C₄ haloalkyl and wherein each Q is independently selected from—N—, —NH—, —CH—, and —CH₂— provided that nor more than three Q are —N—or —NH—.

In some embodiments of the first or second aspects R^(1b) is

which is optionally substituted by one or more substituents selectedfrom the group consisting of (═S), oxo, halogen, C₁-C₄ alkyl, C₁-C₄haloalkoxy, and C₁-C₄ haloalkyl; and wherein Q¹ is —C— or —N—; Q² is—CH₂—, —NH—, —O—, or —S—; and Q³ is —CH— or —N—. In some embodiments ofthe first or second aspects R^(1b) is

which is optionally substituted by one or more substituents selectedfrom the group consisting of halogen, C₁-C₄ alkyl, C₁-C₄ haloalkoxy andC₁-C₄ haloalkyl and wherein Q¹ is —C— or —N—; Q² is —CH₂—, —NH—, —O—, or—S—; and Q³ is —CH— or —N—.

In some embodiments of the first or second aspects R^(1b) is

which is optionally substituted by one or more substituents selectedfrom the group consisting of (═S), oxo, halogen, C₁-C₄ alkyl, C₁-C₄haloalkoxy, and C₁-C₄ haloalkyl; and wherein Q¹ is —C— or —N—; Q² is—CH₂—, —NH—, —O—, or —S—; and Q³ is —CH— or —N—. In some embodiments ofthe first or second aspects R^(1b) is

which is optionally substituted by one or more substituents selectedfrom the group consisting of halogen, C₁-C₄ alkyl, C₁-C₄ haloalkoxy andC₁-C₄ haloalkyl and wherein Q¹ is —C— or —N—; Q² is —CH₂—, —NH—, —O—, or—S—; and Q³ is —CH— or —N—.

In some embodiments of the first or second aspects R^(1b) is substitutedwith F, Cl, Br, I, —CF₃, —OCF₃, —OH, or C₁-C₄ alkyl.

In some embodiments of the first or second aspects R^(1b) is a9-membered bicyclic cyclic group substituted by oxo and optionallysubstituted by one or more substituents selected from the groupconsisting of halogen, C₁-C₄ alkyl, C₁-C₄ haloalkoxy, and C₁-C₄haloalkyl.

In some embodiments of the first or second aspects R^(1b) is

and wherein

is optionally substituted by one or more substituents selected from thegroup consisting of (═S), oxo, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkoxy,and C₁-C₄ haloalkyl. In some embodiments of the first or second aspectsR^(1b) is

and wherein

is optionally substituted by one or more substituents selected from thegroup consisting of oxo, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkoxy, andC₁-C₄ haloalkyl. In some embodiments of the first or second aspectsR^(1b) is

and wherein

is optionally substituted by one or more substituents selected from thegroup consisting of halogen, C₁-C₄ alkyl, C₁-C₄ haloalkoxy, and C₁-C₄haloalkyl.

In a third aspect, Ring C is

In some embodiments of the third aspect Ring C is

wherein each Z is independently CH₂, NH, or O; t is 1 or 2 and at leastone R² is oxo.

In some embodiments of the third aspect t is 2 and the two R² are oxoand phenyl, which is optionally substituted with a fluorine, 1-3halogens or 2-3 halogens of which one is fluorine.

In some embodiments of the third aspect one Z is O and one Z is —CH₂—; tis 2 and both R² are halogens.

In some embodiments of the third aspect X is —CR^(x)— and Ring C is

In a fourth aspect, Ring C is a fused tricyclic cyclic group optionallysubstituted with 1-4 R³.

In some embodiments of the fourth aspect Ring C is optionallysubstituted with 1-4 R³.

Also provided is a pharmaceutical composition comprising atherapeutically effective amount of a compound as claimed in any of theaspects or embodiments herein; and a pharmaceutically acceptablecarrier, excipient, diluent or a mixture thereof.

In some embodiments, the pharmaceutical composition comprises a secondtherapeutic agent selected from the group consisting of: i) opioidreceptor agonists, ii) opioid receptor antagonists, iii) calcium channelantagonists, iv) 5-HT receptor agonists, v) 5-HT receptor antagonistsvi) sodium channel antagonists, vii) NMDA receptor agonists, viii) NMDAreceptor antagonists, ix) COX-2 selective inhibitors, x) neurokininreceptor antagonists, including NK1 antagonists, xi) non-steroidalanti-inflammatory drugs, xii) selective serotonin reuptake inhibitors,xiii) selective serotonin and norepinephrine reuptake inhibitors, xiv)tricyclic antidepressant drugs, xv) norepinephrine modulators, xvi)5-lipoxygenase inhibitors, xvii) cannabinoid receptor agonists, xviii)inhibitors of fatty acid amide hydrolase, ixx) beta-adrenergic receptoragonists, x) prostanoid receptor antagonists, xxi) leukotriene receptorantagonists, xxii) histamine receptor antagonists, xxiii) steroids,xxiv) CGRP antagonists, xxv) peroxisome proliferator-activated receptor(PPAR) agonists, and xxvi) acetaminophen.

Also provided is a method of treating or preventing pain comprisingadministering to a patient in need thereof a therapeutically effectiveamount, or a prophylactically effective amount, of a disclosed compound.In some embodiments the pain treated comprises acute pain, nociceptivepain, inflammatory pain, neuropathic pain, and periprocedural pain(e.g., post-surgical). In some embodiments the neuropathic pain isdiabetic peripheral neuropathic pain or chemotherapeutic-inducedperipheral neuropathic pain.

In some embodiments the method of treating further comprisesadministering a second therapeutic agent selected from the groupconsisting of: i) opioid receptor agonists, ii) opioid receptorantagonists, iii) calcium channel antagonists, iv) 5-HT receptoragonists, v) 5-HT receptor antagonists vi) sodium channel antagonists,vii) NMDA receptor agonists, viii) NMDA receptor antagonists, ix) COX-2selective inhibitors, x) neurokinin receptor antagonists, including NK1antagonists, xi) non-steroidal anti-inflammatory drugs, xii) selectiveserotonin reuptake inhibitors, xiii) selective serotonin andnorepinephrine reuptake inhibitors, xiv) tricyclic antidepressant drugs,xv) antiepileptic drugs, xvi) 5-lipoxygenase inhibitors, xvii)cannabinoid receptor agonists, xviii) inhibitors of fatty acid amidehydrolase (FAAH), ixx) beta-adrenergic receptor agonists, xx) prostanoidreceptor antagonists, xxi) leukotriene receptor antagonists, xxii)histamine receptor antagonists, xxiii) steroids, xxiv) CGRP antagonists,xxv) peroxisome proliferator-activated receptor (PPAR) agonists, andxxvi) acetaminophen.

In some embodiments the 5-HT receptor agonist is a 5-HT_(1B) receptoragonist or a 5HT_(1D) receptor agonist. In some embodiments the 5-HTreceptor agonist is a triptan. In some embodiments the triptan issumatriptan, rizatriptan, naratriptan, zolmitriptan, eletriptan,almotriptan, or frovatriptan.

In some embodiments the opioid receptor agonist is morphine, codeine,oxymorphone, pentazocine, fentanyl, sufentanil, tramadol, meperidine,methadone, or etorphine. In some embodiments the opioid receptor agonistis morphine, codeine, hydrocodone, oxycodone, hydromorphone,oxymorphone, pentazocine, fentanyl, sufentanil, alfentanil, tramadol,O-desmethyltramadol, tapentadol, cebranopadol, ciramdol, meperidine,methadone, nalbuphine, buprenorphine, or etorphine.

In some embodiments the nonsteroidal anti-inflammatory drug (NSAID) isaspirin, ibuprofen, naproxen, ketoprofen, dexketoprofen, loxoprofen,flurbiprofen, oxaprozin, fenoprofen, indomethacin, ketorolac, sulindac,etodolac, diclofenac, aceclofenac, mefanamic acid, meclofenamic acid,flufenamic acid, tolfenamic acid, piroxicam, meloxicam, tenoxicam,salicylic acid, nabumetone, or phenylbutazone. In some embodiments theNSAID is aspirin, ibuprofen, naproxen, ketoprofen, loxoprofen,meloxicam, or diclofenac.

In some embodiments the COX-2 inhibitor is celecoxib, etoricoxib,lumiracoxib, parecoxib, rofecoxib, or valdecoxib.

Also provided is a method of treating or preventing pain before, duringor after surgical procedure, comprising the step of administering to apatient in need thereof a therapeutically effective amount, or aprophylactically effective amount, of a disclosed compound.

III. Pharmaceutical Compositions

Pharmaceutical compositions comprising the disclosed compounds are alsoprovided. In a first embodiment, the pharmaceutical composition furthercomprises one or more pharmaceutically acceptable excipients orvehicles, and optionally other therapeutic and/or prophylacticingredients. Such excipients are known to those of skill in the art. Athorough discussion of pharmaceutically acceptable excipients and saltsis available in Remington's Pharmaceutical Sciences, 18th Edition(Easton, Pa.: Mack Publishing Company, 1990). The compositions can beadministered orally, mucosally, parenterally, topically, transdermally,intranasally, intravenously or by inhalation.

Depending on the intended mode of administration, the pharmaceuticalcompositions may be in the form of solid, semi-solid or liquid dosageforms, such as, for example, tablets, suppositories, pills, capsules,powders, liquids, suspensions, creams, ointments, lotions or the like,preferably in unit dosage form suitable for single administration of aprecise dosage. The compositions will include an effective amount of theselected drug in combination with a pharmaceutically acceptable carrierand, in addition, may include other pharmaceutical agents, adjuvants,diluents, buffers, etc.

Pharmaceutical compositions comprise a disclosed compound includingisomers, racemic or non-racemic mixtures of isomers, or pharmaceuticallyacceptable salts or solvates thereof together with one or morepharmaceutically acceptable carriers and optionally other therapeuticand/or prophylactic ingredients.

For solid compositions, conventional nontoxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose,magnesium carbonate and the like.

For oral administration, the composition will generally take the form ofa tablet, capsule, a softgel capsule nonaqueous solution, suspension orsyrup. Tablets and capsules are preferred oral administration forms.Tablets and capsules for oral use will generally include one or morecommonly used carriers such as lactose and corn starch. Lubricatingagents, such as magnesium stearate, are also typically added. Whenliquid suspensions are used, the active agent may be combined withemulsifying and suspending agents. If desired, flavoring, coloringand/or sweetening agents may be added as well. Other optional componentsfor incorporation into an oral formulation herein include, but are notlimited to, preservatives, suspending agents, thickening agents and thelike.

Parenteral administration includes intraarticular, intravesical,intravenous, intramuscular, intradermal, intraperitoneal, intraocular,intravitreal, intrathecal and subcutaneous administration. Thecompositions for parenteral administration include aqueous andnon-aqueous, isotonic sterile injection solutions, which can containantioxidants, buffers, bacteriostats, and solutes that render theformulation isotonic with the physiological fluids of the intendedrecipient, and aqueous and non-aqueous sterile suspensions that caninclude suspending agents, solubilizers, thickening agents, stabilizers,and preservatives.

Another mode of administration of a compound of the present invention isfor use in regional analgesia. Epidural analgesia and spinal analgesiaare commonly employed techniques of providing pain relief during labor,surgical procedures and diagnostic procedures. Epidural analgesia can beadministered by injection into the epidural space or an indwellingcatheter can be directed into the epidural space and the patientreceives a continuous infusion or multiple injections of the compound ofthe present invention. Administration may also encompass a combinationof epidural and spinal analgesia. In addition, administration mayinclude wound infiltration or injection to create a plexus block.

Compositions for topical, inhalation and transdermal routes ofadministration include powders, sprays, ointments, pastes, creams, gels,lotions, solutions, patches and inhalants. The ointments, pastes, creamsand gels may contain, in addition to an a disclosed composition,excipients, such as animal and vegetable fats, oils, waxes, paraffins,starch, tragacanth, cellulose derivatives, polyethylene glycols,silicones, bentonites, silicic acid, talc and zinc oxide, or mixturesthereof. A dry powder formulation or aerosol formulation of thedisclosed compound is useful for pulmonary delivery.

Powders, aerosols and sprays can contain, in addition to a disclosedcompound, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane. Transdermal patches have the added advantageof providing controlled delivery of a disclosed compound to the body.Such dosage forms can be made by dissolving or dispersing the compoundin the proper medium. Absorption enhancers can also be used to increasethe flux of the compound across the skin. The rate of such flux can becontrolled by either providing a rate controlling membrane or dispersingthe compound in a polymer matrix or gel.

Opthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as within the scope of the disclosure.Formulations for opthalmic administration include are generallyformulated as sterile aqueous solutions and to be compatible with theeye. The ophthalmic formulations intended for direct application to theeye are formulated so as to have a pH and tonicity that are compatiblewith the eye. Example pH ranges are 4 to 9, more preferably 5.5 to 8.5,and most preferably 7 to 8. The osmolality of one or more of thedisclosed compounds in the solution is 200 to 350 milliosmoles perkilogram (mOsm/kg), or 250 to 330 mOsm/kg. The use of nonionicosmolality-adjusting agents is preferred. Examples include propyleneglycol, glycerol, xylitol or combinations thereof. Boric acid may alsobe utilized as an osmolality-adjusting agent in the opthalmicformulations. Boric acid, if utilized, will be present in thecompositions as a mixture of ionic and nonionic species. The opthalmicformulations may contain various types of pharmaceutical excipients,such as surfactants, viscosity-modifying agents such ascarboxymethylcellulose, glycerin, polyvinylpyrrolidone, polyethyleneglycol and so on, provided that such excipients are non-ionic. One ormore conventional antimicrobial preservatives, such as benzalkoniumchloride, polyquarternium-1 or EDTA can be present in the opthalmicformulations. The overall composition may include sufficientantimicrobial activity to satisfy USP/FDA/ISO preservative efficacyrequirements. Opthalmic formulations can be made for single ormulti-dose packaging.

The pharmaceutical compositions can be prepared by any of the methodswell known in the art of pharmacy and drug delivery. In general, methodsof preparing the compositions include the step of bringing the activeingredient into association with a carrier containing one or moreaccessory ingredients. The pharmaceutical compositions are typicallyprepared by uniformly and intimately bringing the active ingredient intoassociation with a liquid carrier or a finely divided solid carrier orboth, and then, if necessary, shaping the product into the desiredformulation.

IV. Methods of Treatment

Pain

Provided are methods of treating pain by the disclosed compounds.Exemplary types of pain treated by the provided compounds include (1)acute, chronic, visceral, inflammatory and/or neuropathic painsyndromes; (2) pain resulting from, or associated with, traumatic nerveinjury, nerve compression or entrapment, acute herpetic and postherpeticneuralgia, trigeminal neuralgia, fibromyalgia, diabetic neuropathy,cancer and/or chemotherapy-induced peripheral neuropathy; (3) lower backpain; (4) phantom limb pain; (5) pain resulting from inflammatorydisease, including osteoarthritis, rheumatoid arthritis, juvenilerheumatoid arthritis, gout, neuropathic arthropathy, psoriaticarthritis, ankylosing spondylitis, other spondyloarthropathies,crystalline arthropathies or systemic lupus erythematosus (SLE); (6)headache pain, migraine pain and cluster headache pain; (7) HIV- and HIVtreatment-induced neuropathy, chronic pelvic pain, neuroma pain, complexregional pain syndrome; (8) stroke or neural trauma or (9) cold painsensitivity.

In some embodiments the neuropathic pain is diabetic peripheralneuropathic pain or chemotherapeutic-induced peripheral neuropathic pain(CIPN). CIPN is a painful adverse effect caused by commonly usedchemotherapeutic agents, which include the taxanes (e.g. Abraxane;Paclitaxel), platinum-based compounds (e.g. Eloxatin: oxaliplatin), andnumerous other anti-cancer drugs. Therapeutic consequences of CIPNinclude chemotherapeutic dose reduction, changes in dosing schedules andtermination of treatment leading to decreased survival. Sensory symptomsincluding pain, numbness and tingling are the most common, but theinitial acute peripheral neuropathy observed in CIPN transitions tochronic neuropathic pain in many patients after discontinuation ofchemotherapy. Oxaliplatin-induced peripheral neuropathy appears inalmost all patients rapidly after infusion and is either triggered orexacerbated by cold, indicating a role for a TRP channel in thisprocess. Recent studies have identified TRPA1 channels as a promisingtarget for novel analgesic drugs for treating or preventing induction ofCIPN.

The compounds of the present invention have applications in preventing,reducing or inhibiting acute and/or chronic pain in a variety ofoperative and interventional procedures, including surgical, diagnosticand therapeutic procedures. An interventional procedure is defined asany procedure used for diagnosis or treatment that involves incision;puncture; entry into a body cavity; or the use of ionizing,electromagnetic or acoustic energy.

Also provided is a method of treating a subject suffering from ordiagnosed with a disease, disorder, or medical condition mediated byTRPA1 activity, comprising administering to the subject in need of suchtreatment an effective amount of at least one chemical entity asdisclosed herein.

Respiratory Disorders or Asthma

In some embodiments, the compounds described herein are useful for thetreatment or prevention of respiratory disorders, such as asthma. Suchconditions can affect the lung, pleural cavity, bronchial tubes,trachea, upper respiratory tract as well as the nerves and musclesinvolved in breathing. The airways are densely innervated by sensorynerves, the majority of which are afferent C-fibers. TRPA1 is expressedon bronchopulmonary C-fiber nerve endings. Evidence suggests that TRPA1is a mediator of allergic airway mediated inflammation and can also beactivated by a variety of irritants, and is thus a molecular target forsuppression of inflammation and airway hyper-reactivity in asthma asshown by experimental animal asthma studies.

Respiratory diseases, including asthma, that may be treated with thecompounds described herein include obstructive diseases such as chronicobstructive pulmonary disease (COPD), emphysema, chronic bronchitis,cystic fibrosis, bronchiectasis, bronchiolitis, allergicbronchopulmonary aspergillosis, and tuberculosis; restrictive lungdisease including asbestosis, radiation fibrosis, hypersensitivitypneumonitis, infant respiratory distress syndrome, idiopathic pulmonaryfibrosis, idiopathic pulmonary fibrosis, idiopathic interstitialpneumonia sarcoidosis, eosinophilic pneumonia, lymphangioleiomyomatosis,pulmonary Langerhan's cell histiocytosis, and pulmonary alveolarproteinosis; respiratory tract infections including upper respiratorytract infections (e.g., common cold, sinusitis, tonsillitis, pharyngitisand laryngitis) and lower respiratory tract infections (e.g.,pneumonia); pleural cavity diseases (e.g., emphysema and mesothelioma);and pulmonary vascular diseases (e.g, pulmonary embolism, pulmonaryarterial hypertension, pulmonary edema). Other conditions that may betreated include disorders that affect breathing mechanics (e.g.,obstructive sleep apnea, central sleep apnea, amyotrophic lateralsclerosis, and myasthenia gravis). The present compounds can also beuseful for treating, reducing, or preventing one or more symptomsassociated with respiratory conditions including, for example, shortnessof breath or dyspnea, cough, chest pain including pleuritic chest pain,noisy breathing, wheezing, and cyanosis. Other conditions include cough,as well as allergy-induced cough and angiotensin converting enzymeinhibitor-induced cough.

Dermatological Diseases and Pruritus

In some embodiments, the compounds described herein are useful for thetreatment or prevention of dermatological diseases and conditions,including pruritus, and atopic dermatitis. Influx of calcium acrossplasma membrane of skin cells is a critical signaling element involvedin cellular differentiation in the skin epidermis. Regulating ormodulating the calcium entry pathway, can be a critical control pointfor skin cell growth, and can treat or prevent skin diseases ordisorders that are characterized by epidermal hyperplasia, a conditionin which skin cells both proliferate too rapidly and differentiatepoorly.

TRPA1 is known to be expressed in human keratinocytes as well as nervefibers in the skin and thus compounds of the present invention can beused for controlling calcium entry through TRPA1. Such diseases includepsoriasis, atopic dermatitis, and basal and squamous cell carcinomas.Psoriasis, estimated to affect up to 7 million Americans, afflictssufferers with mild to extreme discomfort, enhanced susceptibility tosecondary infections, and psychological impact due to disfigurement ofthe affected areas (Lebwohl and Ali, 2001 J. Am. Acad. Dermatol.45:487-498).

Many dermatological disorders are accompanied by itch (pruritus).Chronic debilitating pruritus is a cardinal feature of atopic dermatitis(AD). An IL-13 transgenic mouse model can be utilized to demonstrate theefficacy of compounds of the present invention in inhibiting itch evokedscratching in AD (Oh, et al., 2013, J. Immunol. 191: 5371-5382).Pruritus and pain share many overlapping mediators and receptors, andmechanistic similarities. Decreasing neuronal excitability, particularlyC-fiber excitability may alleviate pruritus associated with dialysis,dermatitis, pregnancy, poison ivy, allergy, dry skin, chemotherapy andeczema. Toll-like receptors may also mediate activation of TRPA1 tocause itch. Hence, TRPA1 antagonists of the present invention,compositions and methods provided herein may also be used in connectionwith treatment of psoriasis, atopic dermatitis and other dermatologicaldiseases.

Inflammatory Diseases and Disorders

In some embodiments, compositions and methods provided herein may alsobe used in connection with treatment of inflammatory diseases. Thesediseases include but are not limited to rheumatoid arthritis,osteoarthritis, inflammatory bowel disease, Crohn's disease, ulcerativecolitis, glomerulonephritis, neuroinflammatory diseases such as multiplesclerosis, periodontitis, and disorders of the immune system.

Peripheral neuropathy, for example diabetic neuropathy, is a particularcondition that involves both a neuronal and an inflammatory component.Without being bound by a mechanistic theory, the TRPA1 antagonists ofthe invention may be useful in treating peripheral neuropathiesincluding, but not limited to, diabetic neuropathy. In addition to theiruse in the treatment of peripheral neuropathies (e.g., reducinginflammation), the subject inhibitors may also be useful in reducing thepain associated with peripheral neuropathy.

Neurogenic inflammation often occurs when neuronal hyperexcitabilityleads to the release of peptides that trigger inflammation. Thesepeptides include substance P and CGRP. Blocking TRPA1 activation onnociceptive nerve endings will reduce neuronal activity and thus blockneurogenic inflammation, reducing the levels of substance P or CGRPreleased.

Pancreatitis is an inflammation of the pancreas. Acute pancreatitisusually begins with pain in the upper abdomen that may last for a fewdays. The pain may be severe and may become constant. The pain may beisolated to the abdomen or it may reach to the back and other areas.Severe cases of acute pancreatitis may cause dehydration and low bloodpressure, and may even lead to organ failure, internal bleeding, ordeath. During acute pancreatitis attacks, the blood levels of amylaseand lipase are often increased by at least 3-fold. In some embodiments,the compounds disclosed herein can be used to relieve the painassociated with acute pancreatitis.

Incontinence and Overactive Bladder

Incontinence is a significant social and medical problem affecting bothmen and women. Incontinence has many causes including, but not limitedto, age, pregnancy, radiation exposure, surgery, injury, cancer,enlargement of the prostatic, prostatic hyperplasia, and diseases of thebladder or musculature that supports the urethra. In some embodiments,compounds of the invention can be used to treat incontinence due to anyof the foregoing, as well as incontinence of unknown causes. In someembodiments, the compounds disclosed herein are used to reduce bladderhyperactivity by decreasing the activity of the neurons that innervatethe bladder. In some embodiments, incontinence is accompanied by pain.For example, incontinence incident to bladder cystitis or incontinenceincident to an injury may be accompanied by pain. When incontinence isaccompanied by pain, the compound may be administered to treat bothincontinence and to reduce pain. The compounds may be administeredeither directly to the bladder (intravesically) or systemically, or byother means. Established animal models of incontinence and bladderhyperactivity can be utilized to test and demonstrate efficacy ofcompounds which can modulate abnormal bladder contractility or increasesin the frequency or magnitude of bladder contractions. Since TRPA1 mRNAis expressed in neurons that innervate bladder, inhibiting TRPA1activity with a TRPA1 antagonist may be an effective treatment forbladder hyperreactivty, overactive bladder, and incontinence.

Cold-Temperature Hypersensitity

TRPA1 is known to be activated by cold temperatures in both man androdent species. In some embodiments, compounds of the invention can alsobe used to modulate abnormal thermal sensitivity that occurs in certaindisease states or conditions. Given that TRPA1 channels are thermalresponsive channels involved in the detection and sensation of coldstimuli, TRPA1 antagonists can be used to modulate the abnormalsensations of cool, cold and decreased temperatures that often accompanypain, including neuropathic pain. In some embodiments, compounds of thepresent invention may be useful to modulate the cold-hypersensitivitythat accompanies treatment with anti-cancer drugs.

Allergies

In some embodiments, the compounds disclosed herein can also be used totreat seasonal allergies, e.g., allergic rhinitis.

General Methods

In some embodiments, the compound is administered periprocedurally,which may include perioperatively. In some embodiments, the compound ofthe present invention is administered preprocedurally orpostprocedurally as well as intraprocedurally. In some embodiments, thecompounds of the present invention are administered to a surgical,diagnostic or therapeutic procedure site by techniques well known tothose of ordinary skill in the art. In some embodiments, post-surgicalpain is treated by the methods of the invention.

The methods of treating pain generally comprise administering a compoundof the invention to a subject in need thereof. In some embodiments, themethod of treating pain comprises modulating the activity of TRPA1 (SEQID NO: 1) or a variant thereof (e.g., a variant selected from SEQ IDNOS:2-7) in the subject. Modulating the activity of TRPA1 can includeactivating TRPA1 or inhibiting TRPA1. In some embodiments, the method oftreating pain comprises administering a compound of the invention to asubject and modulating the activity of TRPA1 (SEQ ID NO: 1) in thesubject. In some embodiments, the method of treating pain comprisesadministering a compound of the invention to a subject and inhibitingthe activity of TRPA1 (SEQ ID NO: 1) in the subject.

In some embodiments, compounds of the invention inhibit the activity ofa TRPA1 protein that has a single amino acid substitution relative toSEQ ID NO: 1 that arise from a naturally occurring variant TRPA1 gene.Such variant TRPA1 genes may result from single nucleotide polymorphism(SNP) sequences which comprise a TRPA1 SNP variant in such a subject.Examples of human SNP variants include, but are not limited to TRPA1:R3C, R58T, Y69C, E179K, K186N A366D, E477K, D573A, R797T, S804N, N855S,and H1018R. In some embodiments, the method of treating pain comprisesadministering a compound of the invention to a subject and inhibitingthe activity of a TRPA1 protein that has a single amino acidsubstitution relative to TRPA1 seq ID No:1 that arise from a naturallyoccurring variant TRPA1 gene.

In some embodiments, the treatment of pain comprises administering adisclosed compound and a second compound selected from one or more ofthe following classes: i) opioid receptor agonists, ii) opioid receptorantagonists, iii) calcium channel antagonists, iv) serotonin (5-HT)receptor agonists, v) 5-HT receptor antagonist vi) sodium channelantagonist, vii) NMDA receptor agonists, viii) NMDA receptorantagonists, ix) COX-2 selective inhibitors, x) neurokinin receptorantagonists, including NK1 antagonists, xi) non-steroidalanti-inflammatory drugs (NSAIDs), xii) selective serotonin reuptakeinhibitors, xiii) selective serotonin and norepinephrine reuptakeinhibitors, xiv) tricyclic antidepressant drugs, xv) norepinephrinemodulators, xvi) 5-lipoxygenase inhibitors, xvii) cannabinoid receptoragonists, xviii) inhibitor of fatty acid amide hydrolases, ixx)beta-adrenergic receptor agonists, x) prostanoid receptor antagonists,xxi) leukotriene receptor antagonists, xxii) histamine receptorantagonists, xxiii) steroids, xxiv) CGRP antagonists, xxv) peroxisomeproliferator-activated receptor (PPAR) agonists, xxvi) chemotherapeuticdrugs, and xxvii) acetaminophen.

Examples of 5-HT receptor agonists include 5-HT_(1B) receptor agonistsand 5-HT_(1D) receptor agonists. Examples of 5-HT_(1B) and 5-HT_(1D)receptor agonists include triptans such as sumatriptan, rizatriptan,naratriptan, zolmitriptan, eletriptan, almotriptan, and frovatriptan.Example opioid receptor agonists include morphine, codeine, hydrocodone,oxymorphone, pentazocine, nalbuphine, fentanyl, sufentanil, tramadol,meperidine, methadone, and etorphine. Examples of NSAIDs includeaspirin, ibuprofen, naproxen, ketoprofen, flurbiprofen, loxoprofen,indomethacin, etodolac, diflunisal, ketorolac, nabumetone, oxaprozin,piroxicam, meloxicam, and diclofenac. Examples of COX-2 inhibitorsinclude celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, andvaldecoxib. Examples of PPAR agonists include PPAR-γ subtypes such asthiazolidinediones, examples of which include rosiglitazone,pioglitazone and troglitazone. Useful PPAR agonists also include PPAR-αsubtype agonists. Examples of sodium channel antagonists includelidocaine, bupivacaine, etidocaine, ropivicaine, mepivicaine, procaine,2-chloroprocaine, pramoxine, prilocaine, proparacaine and tetracaine.Examples of chemotherapeutic drugs include paclitaxel, docetaxel,abraxane, taxotere, oxaliplatin, cisplatin, carboplatin, vorinostat,romidepsin, and other histone deacetylase (HDAC) inhibitor drugs.

In some embodiments, the method of treating pain further comprisesadministering an analgesic, antidepressant, anxiolytic, antiemetic,anti-epileptic or anticonvulsant.

The compounds can be administered at any suitable dose in the methods ofthe invention. In general, compounds of the invention are administeredat doses ranging from about 0.01 milligrams to about 100 milligrams perkilogram of a subject's body weight (i.e., about 0.01-100 mg/kg). Thedose of a compound can be, for example, about 0.01-100 mg/kg, or about0.5-50 mg/kg, or about 1-25 mg/kg, or about 2-10 mg/kg. The dose of thecompound can be about 0.01, 0.05, 0.1, 0.25, 0.50, 0.75, 1, 2, 3, 4, 5,10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 85, 90, 95, or100 mg/kg. The dosages can be varied depending upon the particularcompound used, the requirements of the patient, the type and severity ofthe pain being treated, and the particular formulation beingadministered. In general, the dose administered to a patient issufficient to result in a beneficial therapeutic response in thepatient. The size of the dose will also be determined by the existence,nature, and extent of any adverse side-effects that accompany theadministration of the drug in a particular patient. Determination of theproper dosage for a particular situation is within the skill of thetypical practitioner. The total dosage can be divided and administeredin portions over a period of time suitable to treat to the pain.

In some embodiments, the invention sets forth a compound or formulationas set forth in one of the embodiments herein for use in a medicament.In some embodiments, the invention sets forth the use of a compound orformulation as set forth in one of the embodiments herein for themanufacture of a medicament for the treatment of pain (e.g., for one ofthe disorders set forth in the method embodiments herein).

Compounds of the invention can be administered using any of thepharmaceutical compositions described herein. One of skill in the artwill appreciate that type of composition and route of administrationwill depend, in part, on factors such as the type and severity of painbeing treated. In some embodiments, acute pain is treated by parenteralinjection of a solution or suspension of a compound of the invention. Incertain other embodiments, chronic pain is treated by oraladministration of a compound of the invention in a form such as atablet, pill, or capsule.

Administration of compounds of the invention can be conducted for aperiod of time which will vary depending upon the type of pain beingtreated, its severity, and the overall condition of the patient.Administration can be conducted, for example, hourly, every 2 hours,three hours, four hours, six hours, eight hours, or twice dailyincluding every 12 hours, or any intervening interval thereof.Administration can be conducted once daily, or once every 36 hours or 48hours, or at other intervals. Following treatment, a patient can bemonitored for changes in his or her condition and for pain alleviation.The dosage of the compounds can either be increased in the event thepatient does not respond significantly to a particular dosage level, orthe dose can be decreased if an alleviation or absence of pain isobserved, or if unacceptable side effects are seen with a particulardosage.

A therapeutically effective amount of a compound of the invention can beadministered to the subject in a treatment regimen comprising intervalsof at least 1 hour, or 6 hours, or 12 hours, or 24 hours, or 36 hours,or 48 hours between dosages. Administration can be conducted atintervals of at least 72, 96, 120, 168, 192, 216, or 240 hours, or theequivalent amount of days. The dosage regimen can consist of two or moredifferent interval sets. For example, a first part of the dosage regimencan be administered to a subject multiple times daily, daily, everyother day, or every third day. The dosing regimen can start with dosingthe subject every other day, every third day, weekly, biweekly, ormonthly. The first part of the dosing regimen can be administered, forexample, for up to 30 days, such as 7, 14, 21, or 30 days. A subsequentsecond part of the dosing regimen with a different intervaladministration administered weekly, every 14 days, or monthly canoptionally follow, continuing for 4 weeks up to two years or longer,such as 4, 6, 8, 12, 16, 26, 32, 40, 52, 63, 68, 78, or 104 weeks.Alternatively, if pain subsides or generally improves in the patient,the dosage may be maintained or kept at lower than maximum amount. Ifthe pain recurs, the first dosage regimen can be resumed until animprovement is seen, and the second dosing regimen can be implementedagain. This cycle can be repeated multiple times as necessary.

Animal Pain Models for In Vivo Testing

Animal models are useful for understanding the mechanism of pain anddevelopment of effective therapy for its optimal management. Numerouspain models have been developed to simulate clinical pain conditionswith diverse etiology. Development of these models has contributedimmensely in understanding acute and chronic pain and underlyingperipheral mechanisms. This includes the role of TRPA1 in acute andchronic pain models. Based on these animal pain models, research hasresulted in the development of new therapeutic agents for painmanagement, and the preclinical data obtained using these animal modelshave been successively translated to effective pain management inclinical studies. Each animal model has been created with specificmethodology. Data from each different model is interpreted in thecontext of the specific pain model.

Data Analysis for Pain Models

Compounds are evaluated in well characterized in vivo models to assessacute, inflammatory, neuropathic pain and periprocedural (e.g.,post-surgical) pain. Animals are randomly assigned to each treatmentgroup. Results are presented as mean+S.E.M. Percent Reversal iscalculated as (post-dose−pre-dose)/(pre-injury−pre-dose)×100 for eachrat or mouse. 100% corresponds to complete reversal of hyperalgesia orallodynia, equivalent to non-injured values, and 0% corresponds tovalues not different from baseline post-injury. As appropriate, resultsare analyzed using either 1-way ANOVA or 2-way ANOVA (for dose and timepost-dose) test followed by Bonferroni post-tests for multiplecomparisons (Prism, Graph Pad, San Diego, Calif.). ED₅₀ values arecalculated as doses corresponding to a 50% effect (100% effectcorresponding to recovery or reversal to baseline values in the absenceof injury). In general, experimental and control groups contain at leastsix animals per group.

V. Examples Example 1. Synthesis of Compounds of the Invention

For the lettered schemes (e.g., Scheme A), analytical TLC was performedon Merck silica gel 60 F₂₅₄ aluminium-backed plates. Compounds werevisualised by UV light and/or stained with either I₂ or potassiumpermanganate solution followed by heating. Flash column chromatographywas performed on silica gel. ¹H-NMR spectra were recorded on a BrukerAvance-400 MHz spectrometer with a BBO (Broad Band Observe) and BBFO(Broad Band Fluorine Observe) probe. Chemical shifts (δ) are expressedin parts per million (ppm) downfield by reference to tetramethylsilaneas the internal standard. Splitting patterns are designated as s(singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br s(broad singlet). Coupling constants (J) are given in hertz (Hz). LCMSanalyses were performed either on an Acquity BEH C-18 column (2.10×100mm, 1.70 μm) or Acquity HSS-T3 (2.1×100 mm, 1.8 μm) using theElectrospray Ionisation (ESI) technique.

The following solvents, reagents or scientific terminology may bereferred to by their abbreviations:

-   TLC Thin Layer Chromatography-   CDCl₃ Deuterated chloroform-   DCM Dichloromethane-   THF Tetrahydrofuran-   MeOH Methanol-   EtOH Ethanol-   IPA Isopropanol-   EtOAc Ethyl acetate-   Et₂O Diethyl ether-   DMF N,N-Dimethylformamide-   TEA/Et₃N Triethylamine-   DIPEA Diisopropylethylamine (Hunig's base)-   LiHMDS Lithium bis(trimethylsilyl)amide-   HATU    N,N,N,N-Tetramethyl-O-(7-azabenzotriazol-1-1)uroniumhexafluorophosphate-   AcOH Acetic acid-   TFA Trifluoroacetic acid-   NBS N-Bromosuccinimide-   mL milliliters-   mmol millimoles-   h hour or hours-   min minute or minutes-   g grams-   mg milligrams-   L microliters-   M molar concentration-   M micromolar concentration-   m micrometer or micron-   N Normal concentration-   eq equivalents-   rt or RT Room temperature, ambient, about 27° C.-   MS Mass spectrometry-   Hz Hertz

In the below schemes like-numbered compounds are not necessarily thesame. Numbering restarts with each scheme.

The disclosed compounds can be made by the following general scheme A.

This scheme may be modified to provide the various rings A and B as wellas ring C or —N(R^(N))(R^(C)) of the disclosed compounds by replacingthe various starting materials with those that provide the desired ringsor —N(R^(N))(R^(C)). Using the below Scheme A-1 in place of A,compositions with a substitution on the 4-position of the pyrazole (suchas —CH₃) as shown here, can be made.

In one embodiment, compounds can be prepared according to Scheme B.

Preparation of ethyl 2,4-dioxo-4-(pyridin-4-yl)butanoate (B-2)

A solution of 4-acetyl pyridine (10.0 g, 82.55 mmol) in diethyl ether(160 mL) was cooled to −78° C. followed by addition of LiHMDS (15.16 g,90.80 mmol). The resulting reaction mixture was stirred at −78° C. for45 min followed by dropwise addition of diethyl oxalate in about 30 min.The reaction mixture was then left to stir at room temperature for 16 h.After completion of the reaction (TLC and MS monitoring), the solutionwas then cooled 0° C. and the resulting precipitate was filtered to getthe desired product as an off-white solid (18.0 g, 98%), which wascarried forward to the next step without purification. ¹H-NMR (400 MHz,DMSO-d₆): δ 8.66 (d, J=4.80 Hz, 2H), 7.70 (d, J=5.20 Hz, 2H), 6.43 (s,1H), 4.15 (q, J=7.20 Hz, 2H) and 1.25 (t, J=7.20 Hz, 3H).

Preparation of ethyl 1-phenyl-5-(pyridin-4-yl)-1H-pyrazole-3-carboxylate(B-3)

To a solution of ethyl 2,4-dioxo-4-(pyridin-4-yl)butanoate B-2 (18 g,81.45 mmol) in EtOH (500 mL) was added phenyl hydrazine hydrochloride(9.68 g, 89.59 mmol) and acetic acid (140.0 mL). The resulting reactionmixture was stirred at 90° C. for 3-4 h. After completion the reaction(TLC monitoring) the solvent was evaporated and the residue was directlypurified over silica gel (100-200 Mesh, 10% EtOAc-hexane) to get thedesired product (8.0 g, 33%). ¹H-NMR (400 MHz, DMSO-d₆): δ 8.55 (d,J=6.0 Hz, 2H), 7.51 (m, 3H), 7.38 (m, 3H), 7.24 (m, 2H), 4.35 (q, J=7.20Hz, 2H) and 1.32 (t, J=7.20 Hz, 3H).

Preparation of 1-phenyl-5-(pyridin-4-yl)-1H-pyrazole-3-carboxylic acid(B-4)

To an ice-cold solution of ethyl1-phenyl-5-(pyridin-4-yl)-1H-pyrazole-3-carboxylate B-3 (5.50 g, 18.77mmol) in EtOH (110 mL) was added dropwise an aqueous solution of sodiumhydroxide (2.25 g dissolved in 5.50 mL H₂O). The resulting solution wasstirred at room temperature for 4 h. After completion of the reaction(TLC monitoring), the solvent was evaporated, added H₂O to the residuefollowed by extraction with EtOAc (2×100 mL). The organic layer wasdiscarded and the pH of the aqueous layer was adjusted to ˜4-5 by adding1N HCl followed by extraction with EtOAc (3×200 mL). The combinedorganics were dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to get the desired product (3.0 g, 61%) as awhite solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 13.11 (br s, 1H), 8.55 (d,J=5.60 Hz, 2H), 7.50 (m, 3H), 7.38 (m, 2H), 7.31 (s, 1H) and 7.23 (d,J=6.0 Hz, 2H).

Preparing Final Compounds Having Pyridinyl Ring A and Phenyl Ring B

Method 1:

To an ice-cold solution of1-phenyl-5-(pyridin-4-yl)-1H-pyrazole-3-carboxylic acid 4 (0.10 g, 0.38mmol, 1.0 eq), in DMF (2.0 mL) was added DIPEA (0.145 g, 1.13 mmol, 3.0eq) and HATU (0.214 g, 0.56 mmol, 1.50 eq). The resulting mixture wasstirred under nitrogen atmosphere at 0° C. for 15 min followed byaddition of the respective amine (2.0 eq). The reaction mixture was thenstirred at room temperature for 4-6 h. After the completion of thereaction (TLC monitoring), the solution was diluted with ice cold water(30 mL) followed by extraction with EtOAc (3×50 mL). The combinedorganics were washed with brine, dried over anhydrous Na₂SO₄, filteredand concentrated under reduced pressure. The crude residue was purifiedover silica gel (100-200 Mesh, 1-5% MeOH-DCM) to give the desiredproducts generally in good to excellent yields (18-96%). Individualyields and solvent systems are shown in Table 1. Compounds 14, 31, 38and 39 were directly obtained after the work-up by tritrating theresidue with the solvents disclosed in Table 1. Compound 40 was purifiedvia prep-TLC using the solvent system 5% MeOH-DCM.

Method 2:

To an ice-cold solution of1-phenyl-5-(pyridin-4-yl)-1H-pyrazole-3-carboxylic acid 4 (0.10 g, 0.38mmol, 1.0 eq) in DMA (5 mL) was added methanesulfonyl chloride (0.129 g,1.13 mmol, 3.0 eq) and 2,6-lutidine (0.12 g, 1.13 mmol, 3.0 eq)dropwise. The resulting mixture was stirred under nitrogen atmosphere at0° C. for 15 min followed by addition of the respective amine (1.30 eq)and then left to stir at 50° C. for 6 h. After completion of thereaction (TLC monitoring), the solution was then cooled to roomtemperature, diluted with ice-cold water (25-50 mL) followed byextraction with EtOAc (3×50 mL). The combined organics were washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The crude residue was purified over silica gel(100-200 Mesh, 1-2% MeOH-DCM) to give the desired products in moderateyields (21-54%). Individual yields and the solvent system in which thecompounds were eluted are in Table 1.

Method 3:

A mixture of 1-phenyl-5-(pyridin-4-yl)-1H-pyrazole-3-carboxylic acid 4(0.10 g, 0.38 mmol, 1.0 eq) and SOCl₂ (0.15 g, 1.13 mmol, 3.0 eq) washeated to 90° C. for 2 h. After the completion of the reaction (TLCmonitoring by adding MeOH to convert it to Me ester), the reactionmixture was concentrated under reduced pressure. Meanwhile in another RBflask, to an ice-cold solution of corresponding amine (1.50 eq withrespect to the acid) in THF (5 mL) was added NaH (1.50 eq with respectto the acid or 1.0 eq with respect to the amine). The reaction mixturewas stirred at room temperature for 1 h followed by addition of asolution of acid chloride thus generated in THF. The resulting reactionmixture was stirred at room temperature for 5-6 h. After the completionof the reaction (TLC monitoring), the reaction mass was quenched withice-cold water and extracted with EtOAc (3×50 mL). The combined organicswere washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude residue was purified oversilica gel (100-200 Mesh, 2-5% MeOH-DCM) to give the desired products inmoderate yields (10-15%). Individual yields and the solvent system inwhich the compounds were eluted is provided in Table 1.

Analytical Instrument Details: The ¹H-NMR spectra were obtained onBruker 400 MHz spectrometer, while the LCMS analyses were performed onan Acquity C-18 column (2.10 mm×100 mm, 1.70 m) using the electrosprayionization (ESI) technique (make: Waters). Chemical shifts (6) areexpressed in parts per million (ppm) downfield by reference totetramethylsilane as the internal standard. Splitting patterns aredesignated as s (singlet), d (doublet), t (triplet), q (quartet), m(multiplet) and br s (broad singlet). Coupling constants (J) are givenin Hz.

Table 1 shows tabulated data of the final compounds including the methodby which the final compounds were synthesized. The amines used inpreparing the below compounds (via Methods 1, 2 or 3) are commerciallyavailable or can be synthesized by one of ordinary skill.

TABLE 1 Exemplary Compounds Cpd. Purification NMR data (DMSO-d₆, IDStructure Method Yield technique LCMS 400 MHz)  4

1 36% Column chromatog- raphy (2% MeOH-DCM) 387.21 (M + H)⁺, 97.49% 8.50(d, J = 4.80 Hz, 2H), 7.48 (m, 3H), 7.36 (m, 2H), 7.30 (d, J = 4.80 Hz,2H), 7.07 (s, 1H), 3.93 (m, 2H), 3.76 (m, 2H), 1.67 (m, 4H) and 1.55-1.60 (m, 8H)  6

1 26% Column chromatog- raphy (1-2% MeOH-DCM) 359.20 (M + H)⁺, 96.08%8.55 (d, J = 5.20 Hz, 2H), 7.48 (m, 3H), 7.36 (m, 2H), 7.22 (m, 3H),4.36 (s, 2H), 3.89 (s, 2H), 1.78 (br s, 4H) and 1.57 (br s, 4H)  8

1 39% Column chromatog- raphy (2-5% MeOH-DCM) 479.23 (M + H)⁺, 97.60%8.84 (br s, 1H), 8.56 (d, J = 5.60 Hz, 2H), 7.46 (m, 3H), 7.37 (m, 2H),7.19-7.25 (m, 5H), 6.75 (m, 3H), 4.56-4.61 (m, 3H), 4.50 (m, 1H), 3.87(m, 1H), 3.52 (m, 1H), 2.55 (m, 2H) and 1.75 (m, 2H) 12

1 43% Column chromatog- raphy (1-2% MeOH-DCM) 389.22 (M + H)⁺, 93.94%8.55 (d, J = 5.20 Hz, 2H), 7.54 (m, 3H), 7.48 (m, 2H), 7.23 (m, 2H),7.13 (s, 1H), 4.07 (m, 1H), 3.96 (m, 1H), 3.66-3.76 (m, 3H), 3.40 (m,1H), 1.87 (m, 2H), 1.69 (m, 2H) and 1.59 (m, 4H) 13

1 35% Column chromatog- raphy (2-5% MeOH-DCM) 402.23 (M + H)⁺, 96.39%8.55 (d, J = 5.20 Hz, 2H), 7.63 (br s, 1H), 7.49 (m, 3H), 7.37 (m, 2H),7.24 (d, J = 5.20 Hz, 2H), 7.15 (s, 1H), 4.32-4.46 (m, 2H), 3.40 (m,1H), 3.19 (m, 2H), 3.08 (m, 1H), 2.03 (m, 2H), 1.60-1.70 (m, 2H) and1.40-1.48 (m, 2H) 16

1 20% Column chromatog- raphy (2% MeOH-DCM) 425.19 (M + H)⁺, 97.81% 8.55(m, 2H), 7.49 (m, 3H), 7.37 (m, 2H), 7.23 (m, 2H), 7.14 (s, 1H),3.93-4.14 (m, 4H), 3.71 (m, 1H), 3.43 (m, 1H), 2.38 (m, 2H) and 1.76 (m,4H) 18

1 96% Column chromatog- raphy (2-5% MeOH-DCM) 402.20 (M + H)⁺, 97.0%8.55 (d, J = 4.80 Hz, 2H), 7.57 (br s, 1H), 7.48 (m, 3H), 7.37 (m, 2H),7.23 (d, J = 5.20 Hz, 2H), 7.13 (s, 1H), 3.95-3.98 (m, 1H), 3.75 (m,2H), 3.52 (m, 1H), 3.12 (br s, 2H), 2.13 (br s, 2H) and 1.59 (br s, 4H)25

1 61% Column chromatog- raphy (2-5% MeOH-DCM) 465.22 (M + H)⁺, 95.79%10.86 (br s, 1H), 8.56 (d, J = 5.60 Hz, 2H), 7.48 (m, 3H), 7.37 (m, 2H),7.18-7.25 (m, 4H), 6.96 (m, 3H), 4.70-4.84 (m, 2H), 4.53 (m, 1H), 3.32(m, 1H), 2.91 (m, 1H), 2.31 (m, 2H) and 1.79 (m, 2H) 28

1 55% Column chromatog- raphy (2% MeOH-DCM) 434.23 (M + H)⁺, 98.27% 8.61(d, J = 5.60 Hz, 2H), 7.58 (d, J = 7.60 Hz, 2H), 7.31-7.50 (m, 8H), 7.32(d, J = 6.0 Hz, 2H), 7.26 (s, 1H), 4.89 (m, 1H), 4.77 (m, 1H), 3.49 (m,1H), 3.10 (m, 1H), 2.25 (m, 2H) and 2.10 (m, 2H) 29

1 33% Column chromatog- raphy (2-5% MeOH-DCM) 424.18 (M + H)⁺, 94.76%10.91 (br s, 1H), 8.80 (d, J = 4.40 Hz, 1H), 8.58 (d, J = 4.80 Hz, 2H),7.84 (t, J = 8.0 Hz, 1H), 7.58 (m, 4H), 7.47 (m, 3H), 7.29 (d, J = 5.20Hz, 2H) and 3.02 (s, 3H) 30

1 22% Column chromatog- raphy (2-5% MeOH-DCM) 417.18 (M + H)⁺, 98.45%8.54-8.67 (m, 4H), 7.48 (m, 3H), 7.38 (m, 2H), 7.19-7.23 (m, 3H), 4.47(d, J = 8.40 Hz, 1H), 4.33 (d, J = 8.80 Hz, 1H), 3.60 (m, 1H), 3.28 (m,1H), 1.84 (m, 2H) and 1.69 (m, 2H) 31

1 77% Triturating with n-pentane 391.19 (M + H)⁺, 98.18% 8.55 (d, J =5.20 Hz, 2H), 7.48 (m, 3H), 7.37 (m, 2H), 7.23 (d, J = 5.20 Hz, 2H),7.16 (s, 1H), 3.92 (m, 6H), 3.71 (m, 2H) and 1.69 (m, 4H) 32

1 24% Column chromatog- raphy (2% MeOH-DCM) 479.22 (M + H)⁺, 99.12% 8.56(d, J = 5.60 Hz, 2H), 8.43 (s, 1H), 7.84 (d, J = 8.40 Hz, 1H), 7.49 (m,3H), 7.40 (m, 2H), 7.22- 7.25 (m, 3H), 6.99 (d, J = 8.80 Hz, 1H), 4.11(br s, 2H) and 3.72 (br s, 6H) 33

1 57% Column chromatog- raphy (2% MeOH-DCM) 546.24 (M + H)⁺, 98.67% 8.56(d, J = 3.60 Hz, 2H), 7.50 (m, 5H), 7.40 (m, 2H), 7.33 (s, 1H), 7.22-7.25 (m, 3H), 4.17 (br s, 2H), 3.82 (br s, 2H) and 3.46-3.49 (m, 4H) 34

1 50% Column chromatog- raphy (2% MeOH-DCM) 479.22 (M + H)⁺, 92.47% 8.56(m, 3H), 8.11 (d, J = 7.60 Hz, 1H), 7.50 (m, 3H), 7.40 (m, 2H), 7.24 (m,3H), 7.19 (s, 1H), 4.08 (br s, 2H), 3.81 (br s, 2H) and 3.25 (br s, 4H)35

3 15% Column chromatog- raphy (2-5% MeOH-DCM) 492.09 (M + H)⁺, 95.88%12.70 (br s, 1H), 8.60 (d, J = 5.20 Hz, 2H), 8.18 (d, J = 8.0 Hz, 2H),7.97 (s, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.59 (s, 1H), 7.46- 7.52 (m, 5H)and 7.28 (d, J = 5.20 Hz, 2H) 36

1 88% Column chromatog- raphy (2-5% MeOH-DCM) 403.16 (M + H)⁺, 98.74%9.13 (s, 1H), 8.56 (d, J = 4.80 Hz, 2H), 8.47 (s, 1H), 7.53 (m, 3H),7.44 (m, 2H), 7.38 (s, 1H), 7.27 (d, J = 4.80 Hz, 2H), 3.39 (s, 3H) and3.24 (s, 3H) 37

3 10% Column chromatog- raphy (2-5% MeOH-DCM) 510.12 (M + H)⁺, 94.04%12.67 (br s, 1H), 8.60 (d, J = 5.20 Hz, 2H), 8.34 (m, 2H), 7.96 (s, 1H),7.46-7.65 (m, 7H) and 7.27 (d, J = 5.20 Hz, 2H) 38

1 19% Triturating with diethyl ether- MeOH (1:1) 426.12 (M + H)⁺, 96.14%11.71 (br s, 1H), 10.58 (br s, 1H), 8.57 (d, J = 5.60 Hz, 2H), 8.50 (s,1H), 8.14 (d, J = 6.40 Hz, 1H), 7.52 (m, 3H), 7.48 (m, 2H), 7.41 (s,1H), 7.28 (d, J = 5.20 Hz, 2H) and 7.16 (d, J = 4.80 Hz, 1H) 39

1 70% Triturating with n-pentane and diethyl ether (1:1) 412.14 (M +H)⁺, 96.25% 10.37 (br s, 1H), 8.57 (d, J = 5.60 Hz, 2H), 7.82 (s, 1H),7.53 (m, 4H), 7.47 (m, 2H), 7.39 (s, 1H), 7.26-7.31 (m, 3H) and 3.33 (s,3H) 40

1 44% Prep-TLC (5% MeOH-DCM) 424.11 (M + H)⁺, 99.70% 10.90 (br s, 1H),8.57 (d, J = 6.0 Hz, 2H), 8.42 (d, J = 1.20 Hz, 1H), 8.22 (dd, J = 1.60and 8.0 Hz respectively, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.54 (m, 3H),7.46-7.50 (m, 3H), 7.27 (m, 2H) and 3.02 (s, 3H)

General Procedure for the Preparation of Compounds C-2 (i, l):

A solution of compound C-1 (i, l) (1 eq) in diethyl ether was cooled to−78° C. followed by addition of LiHMDS (1.10 eq). The resulting reactionmixture was stirred at −78° C. for 45 min followed by dropwise additionof diethyl oxalate (1.20 eq) in about 30 min. The reaction mixture wasthen left to stir at room temperature for 16 h. After completion of thereaction (TLC and MS monitoring), the solution was then cooled 0° C. andthe resulting precipitate was filtered to get the desired product asoff-white solids C-2 (i, l), which were carried forward to the next stepwithout purification.

4-Ethoxy-3,4-dioxo-1-(pyridin-3-yl)but-1-en-1-olate Lithium Salt (C-2i)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.97 (s, 1H), 7.70 (s, 1H), 8.14 (m, 1H),7.43 (m, 1H), 6.41 (s, 1H), 4.13 (q, J=6.8 Hz, 2H) and 1.23 (t, J=7.2Hz, 3H). MS: 220.12 (M−H)⁺. Yield: 88%.

1-(3,5-Dimethylpyrazin-2-yl)-4-ethoxy-3,4-dioxobut-1-en-1-olate LithiumSalt (C-2l)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.40 (s, 1H), 6.35 (s, 1H), 4.12 (q, J=7.2Hz, 2H), 2.55 (s, 3H), 2.32 (s, 3H) and 1.21 (t, J=6.8 Hz, 3H). MS:249.09 (M−H)⁺. Yield: 96%.

General Procedure for the Preparation of Compounds C-3 (i, l):

To an ice-cold solution of compound C-2 (i, l), (1.0 eq) in IPA wasadded (4-(trifluoromethyl)phenyl) hydrazine (1.10 eq) and TFA (2.0 eq).The resulting reaction mixture was warmed up to room temperature andthen stirred at 90° C. for 4-5 h. After completion of the reaction (TLCmonitoring), the solvent was evaporated and the residue was diluted withwater and extracted with ethyl acetate (3 times). The combined organicswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated. The crude was purified over silica gel (100-200 Mesh,10-15% EtOAc-hexane) to get the desired products C-3 (i, l).

Ethyl5-(pyridin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylate(C-3i)

LCMS: 362.14 (M+H)⁺, 90.26%. Yield: 71%.

Ethyl5-(3,5-dimethylpyrazin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylate(C-3l)

¹H-NMR (400 MHz, CDCl₃): δ 8.46 (s, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.44(d, J=8.0 Hz, 2H), 7.33 (s, 1H), 3.99 (q, J=7.20 Hz, 2H), 2.43 (s, 3H),2.26 (s, 3H) and 1.15 (t, J=7.2 Hz, 3H). Yield: 26%.

General Procedure for the Preparation of Compounds C-4 (i, l):

To an ice-cold solution of compound C-3 (i, l) (1.0 eq) in EtOH, anaqueous solution of sodium hydroxide (3.0 eq) was added dropwise. Theresulting solution was stirred at room temperature for 4 h. Aftercompletion of the reaction (TLC monitoring), the solvent was evaporated,H₂O added to the residue followed by extraction with EtOAc (2×100 mL).The organic layer was discarded and the pH of the aqueous layer wasadjusted to ˜6 by adding 1N HCl. The resulting precipitate was filteredand dried under vacuum to get the desired products C-4 (i, l) as whitesolids.

5-(Pyridin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylicAcid (C-4i)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.56 (dd, J=1.6 & 4.8 Hz respectively, 1H),8.52 (d, J=1.6 Hz, 1H), 7.82 (d, J=8.4 Hz, 2H), 7.66 (d, J=8.0 Hz, 1H),7.55 (d, J=8.4 Hz, 2H), 7.40 (m, 1H) and 7.11 (s, 1H). LCMS: 334.11(M+H)⁺, 97.80%. Yield: 83%.

5-(3,5-Dimethylpyrazin-2-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylicAcid (C-4l)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.46 (s, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.44(d, J=8.0 Hz, 2H), 7.33 (s, 1H), 2.43 (s, 3H) and 2.26 (s, 3H). LCMS:363.16 (M+H)⁺, 97.35%. Yield: 67.50%.

General Procedure for the Preparation of Final Compounds C-5 (i, l):

To an ice-cold solution of carboxylic acids C-4 (i, l) (1.0 eq), in DMF(2.0 mL) was added DIPEA (3.0 eq) and HATU (1.50 eq). The resultingmixture was stirred under nitrogen atmosphere at 0° C. for 15 minfollowed by addition of the1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (1.20 eq). Thereaction mixture was then stirred at room temperature for 16 h. Afterthe completion of the reaction (TLC monitoring), the solution wasdiluted with ice-cold water (30 mL) followed by extraction with EtOAc(3×50 mL). The combined organics were washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude residue was purified via prep-TLC using the solvent system 3-5%MeOH-DCM. The final step was performed on a 50-100 mg scale.

In some embodiments,1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one is made accordingto Synthetic Scheme D.

Preparation of 1-benzyl-4-(4-fluorophenylamino)piperidine-4-carbonitrile(D-2)

To an ice-cold solution of 1-benzylpiperidin-4-one (D-1) (25 g, 132.10mmol) in acetic acid (80 mL) was added 4-fluoroaniline (14.0 mL, 145.31mmol) and trimethylsilyl cyanide (26.42 mL, 198.15 mmol). The resultingreaction mass was stirred at RT for 18 h. After completion of thereaction (TLC monitoring), the reaction mass was cooled to 0° C. and thepH adjusted to ˜10 using 5.0 N sodium hydroxide solution. The aqueouspart was extracted with DCM (3×250 mL). The combined organics were driedover anhydrous Na₂SO₄, filtered and concentrated. The crude wastriturated with diethyl ether to get the desired product D-2 (30 g, 75%)as a pale yellow solid. ¹H-NMR (400 MHz, CDCl₃): δ 7.32-7.34 (m, 5H),6.91-6.94 (m, 4H), 3.55 (s, 2H), 3.47 (br s, 1H), 2.81-2.84 (m, 2H),2.39-2.45 (m, 2H), 2.21-2.24 (m, 2H) and 1.87-1.94 (m, 2H). LC-MS:310.13 (M+H)⁺, 96.16%.

Preparation of 1-benzyl-4-(4-fluorophenylamino)piperidine-4-carboxamide(D-3)

To an ice-cold solution of1-benzyl-4-(4-fluorophenylamino)piperidine-4-carbonitrile (D-2) (30 g,97.06 mmol) was added 90% aqueous sulphuric acid (150 mL) and theresulting reaction mixture was stirred at room temperature for 16 h.After completion of the reaction (TLC monitoring), the reaction mass wascooled to 0° C. and the pH adjusted to ˜10 using 5.0 N sodium hydroxidesolution. The aqueous part was extracted with DCM (3×250 mL). Thecombined organics were dried over anhydrous sodium sulphate, filteredand concentrated. The crude was triturated with diethyl ether to get thedesired product D-3 (27 g, 87%) as an off-white solid. ¹H-NMR (400 MHz,CDCl₃): δ 7.23-7.30 (m, 5H), 6.87-6.91 (m, 3H), 6.55-6.59 (m, 2H), 5.47(br s, 1H), 3.93 (s, 1H), 3.48 (s, 2H), 2.72-2.75 (m, 2H), 2.28-2.35 (m,2H), 2.04-2.10 (m, 2H) and 1.86-1.89 (m, 2H). LCMS: 328.12 (M+H)⁺,99.60%.

Preparation of8-benzyl-1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one (D-4)

A solution of 1-benzyl-4-(4-fluorophenylamino)piperidine-4-carboxamide(2.50 g, 7.63 mmol) in triethylorthoformate (3.20 mL) and AcOH (1.20 mL)was irradiated by microwave in a sealed tube to 180° C. for 30 min. Thereaction mixture was diluted with water and extracted with EtOAc (3×100mL). The combined organics were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified over silicagel (100-200 M, 4% MeOH-DCM) to get the desired product D-4 (1.20 g,60%) as a pale yellow solid. LCMS: 338.22 (M+H)⁺, 82.22%.

Preparation of 1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one(D-5)

To a solution of8-benzyl-1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one (1.30g, 3.85 mmol) in MeOH (16 mL) and AcOH (0.40 mL) were added 10% Pd—C(0.34 g) and the resulting solution was stirred under hydrogenatmosphere (1 atm) at ambient temperature for 16 h. The reaction mixturewas filtered through a diatomaceous earth (Celite™) bed and the filtratewas concentrated under reduced pressure to get the desired product D-5(0.95 g, 99%) as an off-white solid, which was used as such for the nextstep without further purification. LCMS: 250.13 (M+H)⁺, 81.19%.

Scheme D can be modified to provide substitutions at positions otherthan the 4-position on the phenyl ring as well as provide substitutionsother than fluorine.

Table 2 shows individual compounds yields for compounds made accordingto schemes C and D:

TABLE 2 Exemplary Compounds Cpd. Yield NMR data (DMSO-d₆, 400 MHz), IDStructure (%) LCMS unless otherwise specified 49

 8 565.46 (M + H)⁺, 95.45% δ 8.80 (br s, 1H), 8.59 (dd, J = 1.60 and4.80 Hz, respectively, 1H), 8.55 (d, J = 2.0 Hz, 1H), 7.83 (d, J = 8.80Hz, 2H), 7.67-7.70 (m, 1H), 7.56 (d, J = 8.40 Hz, 2H), 7.42-7.45 (m,1H), 7.16 (s, 1H), 7.07-7.14 (m, 2H), 6.84-6.88 (m, 2H), 4.59 (d, J =3.20 Hz, 2H), 4.42-4.52 (m, 2H), 3.88 (m, 1H), 3.53 (m, 1H), 2.20- 2.32(m, 2H) and 1.74-1.83 (m, 2H) 52

12 594.45 (M + H)⁺, 99.83% δ 8.81 (br s, 1H), 8.47 (s, 1H), 7.75 (d, J =8.40 Hz, 2H), 7.44 (d, J = 8.40 Hz, 2H), 7.22 (s, 1H), 7.10 (t, J = 8.80Hz, 2H), 6.85-6.88 (m, 2H), 4.59 (d, J = 3.20 Hz, 2H), 4.43-4.51 (m,2H), 3.90 (t, J = 12.40 Hz, 1H), 3.55 (t, J = 10.40 Hz, 1H), 2.43 (s,3H), 2.27-2.32 (m, 5H) and 1.75-1.84 (m, 2H)

In some embodiments, disclosed compounds are made according to Scheme E.

Preparation of ethyl 2,4-dioxo-4-(pyridin-4-yl)butanoate (E-2)

A solution of 4-acetyl pyridine (10.0 g, 82.55 mmol) in di-ethyl ether(160 mL) was cooled to −78° C. followed by addition of LiHMDS (15.16 g,90.80 mmol). The resulting reaction mixture was stirred at −78° C. for45 min followed by dropwise addition of diethyl oxalate (13.5 mL, 98.92mmol) in about 30 min. The reaction mixture was then left to stir atroom temperature for 16 h. After completion of the reaction (TLC and MSmonitoring), the solution was then cooled 0° C. and the resultingprecipitate was filtered to get the desired product as an off-whitesolid (18.0 g, 98%), which was carried forward to the next step withoutpurification.

¹H-NMR (400 MHz, DMSO-d₆): δ 8.66 (d, J=4.80 Hz, 2H), 7.70 (d, J=5.20Hz, 2H), 6.43 (s, 1H), 4.15 (q, J=7.20 Hz, 2H) and 1.25 (t, J=7.20 Hz,3H).

General Procedure for the Preparation of Compounds E-3a-f:

To an ice-cold solution of ethyl 2,4-dioxo-4-(pyridin-4-yl)butanoate E-2(1.0 eq) in IPA was added a respective hydrazine (1.10 eq) and TFA (2.0eq). The resulting reaction mixture was warmed up to room temperatureand then stirred at 90° C. for 4-5 h. After completion of the reaction(TLC monitoring), the solvent was evaporated and the residue was dilutedwith water and extracted with ethyl acetate (3 times). The combinedorganics were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated. The crude was purified over silica gel(100-200 Mesh, 10-15% EtOAc-hexane) to get the desired product.

Ethyl5-(pyridin-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylate(E-3a)

¹H-NMR (400 MHz, CDCl₃): δ 8.61 (d, J=6.0 Hz, 2H), 7.66 (d, J=8.4 Hz,2H), 7.47 (d, J=8.4 Hz, 2H), 7.17 (s, 1H), 7.11 (m, 2H), 4.44 (q, J=7.20Hz, 2H) and 1.41 (t, J=7.20 Hz, 3H). LCMS: 362.21 (M+H)⁺, 99.95%. Yield:50%.

Ethyl 1-(3,4-difluorophenyl)-5-(pyridin-4-yl)-1H-pyrazole-3-carboxylate(E-3b)

¹H-NMR (400 MHz, CDCl₃): δ 8.61 (d, J=6.0 Hz, 2H), 7.31 (m, 1H), 7.30(s, 1H), 7.19 (m, 1H), 7.04 (m, 2H), 7.01 (m, 1H), 4.43 (q, J=7.20 Hz,2H) and 1.39 (t, J=7.20 Hz, 3H). LCMS: 330.14 (M+H)⁺, 93.07%. Yield:55%.

Ethyl1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-4-yl)-1H-pyrazole-3-carboxylate(E-3c)

¹H-NMR (400 MHz, CDCl₃): δ 8.68 (dd, J=1.6 & 4.40 Hz, 2H), 7.60 (m, 1H),7.36 (m, 1H), 7.14 (m, 4H), 4.44 (q, J=7.20 Hz, 2H) and 1.39 (t, J=6.80Hz, 3H). MS: 380.0 (M+H)⁺. Yield: 45%.

Ethyl5-(pyridin-4-yl)-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-3-carboxylate(E-3d)

¹H-NMR (400 MHz, CDCl₃): δ 8.67 (m, 3H), 7.92 (dd, J=2.0 & 8.40 Hz, 1H),7.76 (s, 1H), 7.18 (m, 3H), 4.45 (q, J=7.20 Hz, 2H) and 1.42 (t, J=6.80Hz, 3H). LCMS: 362.89 (M+H)⁺, 98.45%. Yield: 50%.

Ethyl 1-(pyrazin-2-yl)-5-(pyridin-4-yl)-1H-pyrazole-3-carboxylate (E-3e)

¹H-NMR (400 MHz, CDCl₃): δ 9.21 (d, J=1.20 Hz, 1H), 8.62 (m, 2H), 8.60(m, 1H), 8.23 (dd, J=1.2 & 2.40 Hz, 1H), 7.17 (d, J=6.0 Hz, 2H), 7.14(s, 1H), 4.45 (q, J=7.20 Hz, 2H) and 1.42 (t, J=6.80 Hz, 3H). LCMS:296.18 (M+H)⁺, 96.22%. Yield: 30%.

Ethyl5-(pyridin-4-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carboxylate(E-3f)

¹H-NMR (400 MHz, CDCl₃): δ 8.72 (d, J=5.60 Hz, 2H), 7.31 (m, 2H), 7.21(s, 1H), 7.05 (m, 2H), 4.47 (q, J=6.80 Hz, 2H) and 1.43 (t, J=6.80 Hz,3H). MS: 348.12 (M+H)⁺. Yield: 76%.

General Procedure for the Preparation of Compounds E-4a-f:

To an ice-cold solution of compound (E-3a-f) (1.0 eq) in EtOH was addeddropwise an aqueous solution of sodium hydroxide (3.0 eq). The resultingsolution was stirred at room temperature for 4 h. After completion ofthe reaction (TLC monitoring), the solvent was evaporated, H₂O added tothe residue followed by extraction with EtOAc (2×100 mL). The organiclayer was discarded and the pH of the aqueous layer was adjusted to ˜6by adding 1N HCl. The resulting precipitate was filtered and dried undervacuum to get the desired product (60-80%) as a white solid.

5-(Pyridin-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylicAcid (E-4a)

Scaffold A. ¹H-NMR (400 MHz, DMSO-d₆): δ 12.84 (br s, 1H), 8.58 (d,J=5.60 Hz, 2H), 7.87 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 7.28 (m,3H). LCMS: 334.13 (M+H)⁺, 97.98%. Yield: 95%.

1-(3,4-Difluorophenyl)-5-(pyridin-4-yl)-1H-pyrazole-3-carboxylic Acid(E-4b)

Scaffold C. ¹H-NMR (400 MHz, DMSO-d₆): δ 13.17 (br s, 1H), 8.57 (d,J=5.60 Hz, 2H), 7.69 (m, 1H), 7.54 (m, 1H), 7.22 (m, 4H). MS: 302.18(M+H)⁺. Yield: 78%.

1-(3-Fluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-4-yl)-1H-pyrazole-3-carboxylicAcid (E-4c)

Scaffold G. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.60 (d, J=5.6 Hz, 2H), 7.88(m, 1H), 7.67 (s, 1H), 7.32 (m, 4H). LCMS: 352.17 (M+H)⁺, 98.60%. Yield:92%.

5-(Pyridin-4-yl)-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (E-4d)

Scaffold H. ¹H-NMR (400 MHz, DMSO-d₆): δ 13.07 (br s, 1H), 8.81 (s, 1H),8.60 (d, J=6.0 Hz, 2H), 8.05 (m, 2H), 7.34 (m, 3H). LCMS: 335.13 (M+H)⁺,97.97%. Yield: 75%.

1-(Pyrazin-2-yl)-5-(pyridin-4-yl)-1H-pyrazole-3-carboxylic Acid (E-4e)

Scaffold I. ¹H-NMR (400 MHz, DMSO-d₆): δ 13.40 (br s, 1H), 9.15 (s, 1H),8.75 (d, J=6.4 Hz, 1H), 8.56 (m, 2H), 8.43 (s, 1H), 7.33 (s, 3H). LCMS:268.17 (M+H)⁺, 99.0%. Yield: 74%.

5-(pyridin-4-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carboxylic Acid(E-4f)

Scaffold K. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.58 (d, J=5.60 Hz, 2H), 7.58(m, 2H), 7.29 (d, J=6.0 Hz, 2H) and 7.16 (s, 1H). LCMS: 320.09 (M+H)⁺,94.66%. Yield: 91%.

General Procedure for the Preparation of Final Compounds (E-5):

To an ice-cold solution of carboxylic acids E-4 (a-f) (1.0 eq), in DMF(2.0 mL) was added DIPEA (3.0 eq) and HATU (1.50 eq). The resultingmixture was stirred under nitrogen atmosphere at 0° C. for 15 minfollowed by addition of the respective amine (1.20 eq). The reactionmixture was then stirred at room temperature for 16 h. After thecompletion of the reaction (TLC monitoring), the solution was dilutedwith ice-cold water (30 mL) followed by extraction with EtOAc (3×50 mL).The combined organics were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The cruderesidue was purified via prep-TLC using the solvent systems 3-5%MeOH-DCM. The final step was performed on 50-100 mg scale.

Where needed, 1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one ismade according to Synthetic Scheme D. Scheme D can be modified toprovide substitutions at positions other than the 4-position on thephenyl ring as well as provide substitutions other than fluorine. Otheramines used in the preparation of the final compounds illustrated inTable 5 according to Scheme E are commercially available or can besynthesized by one of ordinary skill.

TABLE 5 Exemplary Compounds Yield NMR data (DMSO-d₆, 400 MHz), Cpd IDStructure (%) LCMS unless otherwise specified 54

48% 532.18 (M + H)⁺, 91.71% δ 8.60-8.61 (m, 2H), 7.87 (d, J = 8.40 Hz,2H), 7.61 (d, J = 8.40 Hz, 2H), 7.31 (m, 2H), 7.22-7.26 (m, 3H),7.15-1.17 (m, 1H), 6.97-7.0 (m, 1H), 4.68-4.76 (m, 2H), 4.42 (m, 1H),3.53 (s, 2H), 2.94 (m, 1H), 2.68 (m, 1H), 2.28-2.39 (m, 2H) and 1.59-1.79 (m, 2H) 55

35% 565.19 (M + H)⁺, 94.13% δ 8.80 (br s, 1H), 8.59-8.61 (m, 2H), 7.85(d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.30 (m, 2H), 7.21 (s,1H), 7.09 (t, J = 8.40 Hz, 1H), 6.86 (m, 2H), 4.59 (s, 2H), 4.46 (m,2H), 3.88 (m, 1H), 3.54 (m, 1H), 2.19-2.30 (m, 2H) and 1.74-1.78 (m, 2H)56

31% 581.39 (M + H)⁺, 95.05% δ 8.88 (br s, 1H), 8.61 (d, J = 5.20 Hz,2H), 7.85 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.32 (d, J =5.60 Hz, 2H), 7.24-7.26 (m, 3H), 6.77 (d, J = 8.80 Hz, 2H), 4.61 (s,2H), 4.50 (m, 2H), 3.85-3.90 (m, 1H), 3.51-3.57 (m, 1H), 2.36-2.40 (m,2H) and 1.71-1.81 (m, 2H) 57

53% 505.13 (M + H)⁺, 95.89% δ 8.61 (d, J = 5.60 Hz, 2H), 7.87 (d, J =8.40 Hz, 2H) 7.61 (d, J = 8.40 Hz, 2H), 7.29-7.31 (m, 6H), 7.21 (s, 1H),5.04 (s, 2H), 4.59-4.61 (m, 2H), 3.47-3.54 (m, 1H), 3.11-3.16 (m, 1H),1.90-2.0 (m, 2H) and 1.68-1.77 (m, 2H) 58

56% 519.18 (M + H)⁺, 97.08% δ 8.61 (m, 2H), 7.76-7.88 (m, 5H), 7.60-7.63 (m, 3H), 7.31 (m, 2H), 7.24 (s, 1H), 4.76-4.79 (m, 1H), 4.67-4.70(m, 1H), 3.51-3.57 (m, 1H), 3.14-3.21 (m, 1H), 2.26-2.37 (m, 2H) and1.71-1.80 (m, 2H) 177

37% 569.42 (M + H)⁺, 98.48% δ 11.25 (br s, 1H), 8.61 (d, J = 6.0 Hz,2H), 7.87 (d, J = 8.40 Hz, 2H), 7.61 (d, J = 8.40 Hz, 2H), 7.32 (d, J =6.0 Hz, 2H), 7.22 (s, 1H), 7.0-7.06 (m, 1H), 6.77-6.80 (m, 1H),4.79-4.82 (m, 1H), 4.62-4.70 (m, 2H), 3.32 (m, 1H), 2.93-2.99 (m, 1H),2.11-2.21 (m, 2H) and 1.84-1.92 (m, 2H) 178

25% 601.43 (M + H)⁺, 99.83% δ 11.27 (br s, 1H), 8.61 (d, J = 6.0 Hz,2H), 7.87 (d, J = 8.40 Hz, 2H), 7.61 (d, J = 8.40 Hz, 2H), 7.45-7.48 (m,1H), 7.35- 7.37 (m, 1H), 7.32 (d, J = 6.0 Hz, 2H), 7.23 (d, J = 5.60 Hz,2H), 4.71-4.80 (m, 2H), 4.54-4.60 (m, 1H), 3.32 (m, 1H), 2.93-2.99 (m,1H), 2.29-2.37 (m, 2H) and 1.79-1.90 (m, 2H) 60

52% 518.35 (M + H)⁺, 96.48% (DMSO-d6 @ 373° K.) δ 8.61 (d, J = 6.0 Hz,2H), 7.86 (d, J = 8.40 Hz, 2H), 7.66 (d, J = 8.40 Hz, 2H), 7.31 (d, J =5.60 Hz, 2H), 7.22 (m, 5H), 5.22 (m, 1H), 5.05 (m, 1H), 4.85 (m, 1H),4.60 (m, 1H), 4.25 (m, 1H), 3.46 (m, 1H) and 2.82 (m, 2H) 61

41% 547.18 (M + H)⁺, 93.76% δ 8.61 (m, 2H), 7.87 (d, J = 8.80 Hz, 2H),7.61 (d, J = 8.40 Hz, 2H), 7.31 (m, 3H), 7.23 (s, 1H), 7.15 (m, 1H),7.02-7.06 (m, 2H), 4.70-4.78 (m, 2H), 4.54 (m, 1H), 3.37 (m, 1H), 3.30(m, 2H), 2.97 (m, 2H), 2.30-2.39 (m, 2H) and 1.77-1.86 (m, 2H) 62

47% 562.18 (M + H)⁺, 97.04% δ 8.59 (m, 2H), 7.86 (m, 2H), 7.59 (d, J =8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.40 (m, 5H), 7.26-7.29 (m, 2H),7.06-7.13 (m, 1H), 5.01 (m, 1H), 4.52-4.66 (m, 2H), 4.45 (m, 1H), 3.98(m, 1H), 3.60 (m, 1H), 3.05 (m, 1H), 2.66 (m, 1H), 1.90 (m, 1H),1.56-1.76 (m, 2H) and 1.26 (m, 1H) 63

50% 491.18 (M + H)⁺, 98.64% δ 8.60 (d, J = 5.60 Hz, 2H), 7.87 (d, J =8.40 Hz, 2H), 7.60 (d, J = 8.40 Hz, 2H), 7.30 (m, 2H), 7.18 (s, 1H),3.95 (m, 2H), 3.74 (m, 2H), 3.34 (m, 4H) and 2.09 (m, 4H) 65

81% 518.35 (M + H)⁺, 98.95% δ 8.61 (d, J = 6.0 Hz, 2H), 7.88 (d, J =8.40 Hz, 2H), 7.67-7.71 (m, 2H), 7.61 (d, J = 8.40 Hz, 2H), 7.30-7.38(m, 4H), 7.20 (s, 1H), 4.48-4.56 (m, 2H), 3.40-3.52 (m, 2H), 3.15 (m,1H), 2.21 (m, 2H) and 1.80- 1.88 (m, 2H) 66

41% 489.13 (M + H)⁺, 99.36% δ 10.54 (br s, 1H), 8.61 (m, 2H), 7.90- 7.93(m, 3H), 7.70 (m, 2H), 7.63 (m, 1H), 7.42 (m, 2H) and 7.33 (m, 2H) 67

54% 494.21 (M + H)⁺, 95.76% δ 10.33 (br s, 1H), 8.61 (m, 2H), 7.90- 7.92(m, 2H), 7.70 (m, 2H), 7.53-7.59 (m, 2H), 7.40 (s, 1H), 7.32 (m, 2H),7.15 (m, 1H), 4.65 (s, 2H) and 3.27 (s, 3H) 68

87% 488.18 (M + H)⁺, 98.83% δ 8.92 (br s, 1H), 8.60 (d, J = 4.80 Hz,2H), 7.88 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 7.30 (d, J =5.60 Hz, 2H), 7.18 (s, 1H), 4.40 (m, 1H), 4.24 (m, 1H), 3.55 (m, 4H) and1.94 (m, 4H) 69

51% 521.13 (M + H)⁺, 99.69% δ 10.49 (s, 1H), 8.62 (d, J = 5.60 Hz, 2H),7.97 (d, J = 1.60 Hz, 1H), 7.93 (d, J = 8.40 Hz, 2H), 7.87 (d, J = 8.80Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.42-7.44 (m, 2H), 7.34 (d, J = 6.00Hz, 2H), 3.54 (s, 3H) and 3.52 (s, 3H) 70

27% 465.30 (M + H)⁺, 98.41% δ 10.80 (br s, 1H), 8.63 (d, J = 5.60 Hz,2H), 8.27 (br s, 1H), 7.91-7.97 (m, 3H), 7.85 (m, 1H), 7.72 (d, J = 8.40Hz, 2H), 7.47 (s, 1H), 7.34 (d, J = 6.0 Hz, 2H) and 5.41 (s, 2H) 71

74% 473.24 (M + H)⁺, 98.86% δ 8.60 (d, J = 4.40 Hz, 2H), 7.87 (d, J =7.60 Hz, 2H), 7.60 (d, J = 7.60 Hz, 2H), 7.30 (d, J = 4.40 Hz, 2H), 7.18(s, 1H), 4.22 (m, 1H), 4.07 (m, 1H), 3.86-3.94 (m, 2H), 3.67-3.75 (m,2H), 1.70 (m, 4H) and 1.20 (m, 4H) 72

56% 458.26 (M + H)⁺, 97.18% δ 8.61 (d, J = 6.0 Hz, 2H), 7.88 (d, J =8.40 Hz, 2H), 7.62 (d, J = 8.40 Hz, 2H), 7.29 (m, 2H), 7.22 (s, 1H),4.33-4.79 (m, 3H), 3.89-4.05 (m, 2H), 3.63-3.73 (m, 1H), 3.18-3.21 (m,1H), 3.01-3.10 (m, 1H) and 2.78-2.84 (m, 1H) 73

38% 547.44 (M + H)⁺, 97.83% δ 8.61 (d, J = 6.0 Hz, 2H), 7.87 (d, J =8.40 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.40 Hz, 2H), 7.39(m, 2H), 7.31 (d, J = 6.0 Hz, 2H), 7.20 (s, 1H), 7.13-7.16 (m, 1H),4.73-4.76 (m, 2H), 4.42-4.50 (m, 2H), 3.61 (m, 1H), 3.49 (m, 1H), 3.16(m, 1H) and 1.64-1.80 (m, 4H) 74

50% 501.21 (M + H)⁺, 96.25% δ 8.60 (d, J = 6.0 Hz, 2H), 7.87 (d, J =8.40 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 6.0 Hz, 2H), 7.18(s, 1H), 4.05-4.12 (m, 2H), 3.95 (m, 1H), 3.77-3.86 (m, 2H), 3.62-3.67(m, 1H), 3.51 (m, 1H), 1.69 (m, 4H), 1.28-1.54 (m, 4H) and 0.89 (t, J =6.80 Hz, 3H) 75

71% 499.21 (M + H)⁺, 98.50% δ 8.91 (br s, 1H), 8.61 (d, J = 5.60 Hz,2H), 7.87 (d, J = 8.40 Hz, 2H), 7.61 (d, J = 8.40 Hz, 2H), 7.30 (d, J =6.0 Hz, 2H), 7.21 (s, 1H), 4.44 (m, 1H), 4.34 (m, 1H), 3.62 (m, 1H),3.39 (m, 1H), 2.84 (s, 3H), 1.82-1.88 (m, 2H) and 1.62-1.70 (m, 2H) 76

55% 500.18 (M + H)⁺, 99.18% δ 8.59 (d, J = 6.0 Hz, 2H), 7.68-7.72 (m,1H), 7.52-7.59 (m, 1H), 7.21-7.29 (m, 6H), 7.15-7.17 (m, 1H), 6.99 (m,1H), 4.67-4.77 (m, 2H), 4.42 (m, 1H), 3.53 (s, 2H), 3.39 (m, 1H), 2.93(m, 1H), 2.26- 2.38 (m, 2H) and 1.69-1.79 (m, 2H) 77

34% 533.37 (M + H)⁺, 98.79% δ 8.80 (br s, 1H), 8.59 (d, J = 6.0 Hz, 2H),7.64-7.69 (m, 1H), 7.51-7.58 (m, 1H), 7.28 (d, J = 6.0 Hz, 2H), 7.20 (m,2H), 7.08-7.12 (m, 2H), 6.83-6.87 (m, 2H), 4.58 (s, 2H), 4.41-4.50 (m,2H), 3.86 (m, 1H), 3.53 (m, 1H), 2.18-2.31 (m, 2H) and 1.73-1.82 (m, 2H)78

33% 549.43 (M + H)⁺, 97.25% δ 8.87 (br s, 1H), 8.59 (br s, 2H), 7.68-7.70 (m, 1H), 7.51-7.57 (m, 1H), 7.23- 7.29 (m, 6H), 6.74-6.77 (m, 2H),4.60 (s, 2H), 4.47-4.53 (m, 2H), 3.82-3.88 (m, 1H), 3.50-3.56 (m, 1H),2.35-2.41 (m, 2H) and 1.70-1.80 (m, 2H) 79

81% 473.13 (M + H)⁺, 93.47% δ 8.59 (d, J = 5.60 Hz, 2H), 7.66-7.71 (m,1H), 7.52-7.59 (m, 1H), 7.27-7.32 (m, 6H), 7.23 (m, 1H), 7.19 (s, 1H),5.04 (s, 2H), 4.55-4.61 (m, 2H), 3.43-3.52 (m, 1H), 3.09-3.15 (m, 1H),1.88-1.98 (m, 2H) and 1.68-1.76 (m, 2H) 80

82% 487.17 (M + H)⁺, 95.38% δ 8.60 (d, J = 4.80 Hz, 2H), 7.76-7.86 (m,3H), 7.68-7.72 (m, 1H), 7.53-7.63 (m, 2H), 7.30 (d, J = 5.60 Hz, 2H),7.22 (m, 2H), 4.77-4.80 (m, 1H), 4.66-4.69 (m, 1H), 3.50-3.56 (m, 1H),3.13-3.20 (m, 1H), 2.24-2.28 (m, 2H) and 1.72-1.80 (m, 2H) 82

71% 486.58 (M + H)⁺, 97.21% δ 8.61 (m, 2H), 7.56-7.86 (m, 2H), 7.22-7.39 (m, 8H), 4.50-5.54 (m, 4H), 3.95- 4.42 (m, 1H), 3.45 (m, 1H) and2.79-2.91 (m, 3H) 83

58% 515.19 (M + H)⁺, 96.42% δ 8.59 (d, J = 5.20 Hz, 2H), 7.68-7.72 (m,1H), 7.52-7.59 (m, 1H), 7.28-7.29 (m, 3H), 7.22-7.24 (m, 2H), 7.15 (m,1H), 7.02-7.08 (m, 2H), 4.69-4.79 (m, 2H), 4.55 (m, 1H), 3.30 (s, 3H),2.92-2.98 (m, 2H), 2.28-2.37 (m, 2H) and 1.76-1.85 (m, 2H) 84

34% 530.17 (M + H)⁺, 92.49% δ 8.58 (m, 2H), 7.54-7.71 (m, 2H), 7.40 (m,5H), 7.23-7.26 (m, 3H), 7.05-7.11 (m, 1H), 5.01 (m, 1H), 4.52-4.66 (m,2H), 4.43 (m, 1H), 3.98 (m, 1H), 3.60 (m, 1H), 3.03 (m, 1H), 2.66 (m,1H), 1.90 (m, 1H), 1.56-1.76 (m, 2H) and 1.17 (m, 1H) 85

78% 459.10 (M + H)⁺, 99.41% δ 8.59 (d, J = 4.80 Hz, 2H), 7.70 (m, 1H),7.52-7.59 (m, 1H), 7.27 (d, J = 4.80 Hz, 2H), 7.22 (m, 1H), 7.17 (s,1H), 3.94 (m, 2H), 3.73 (m, 2H), 3.34 (m, 4H) and 2.08 (m, 4H) 87

58% 485.99 (M + H)⁺, 97.66% δ 8.59 (d, J = 6.0 Hz, 2H), 7.67-7.73 (m,3H), 7.53-7.60 (m, 1H), 7.32-7.38 (m, 2H), 7.28 (m, 2H), 7.24 (m, 1H),7.18 (s, 1H), 4.47-4.57 (m, 2H), 3.45 (m, 2H), 3.14 (m, 1H), 2.20 (m,2H) and 1.79-1.90 (m, 2H) 88

57% 457.27 (M + H)⁺, 99.14% δ 10.55 (br s, 1H), 8.60 (d, J = 6.0 Hz,2H), 7.94 (m, 1H), 7.78-7.83 (m, 1H), 7.57-7.64 (m, 2H), 7.39-7.41 (m,2H) and 7.32 (m, 3H) 89

88% 462.31 (M + H)⁺, 98.43% δ 10.34 (br s, 1H), 8.60 (d, J = 6.0 Hz,2H), 7.78-7.83 (m, 1H), 7.54-7.63 (m, 3H), 7.39 (s, 1H), 7.30-7.31 (m,3H), 7.15 (d, J = 8.80 Hz, 1H), 4.65 (s, 2H) and 3.27 (s, 3H) 90

58% 456.30 (M + H)⁺, 99.11% δ 8.92 (br s, 1H), 8.59 (d, J = 6.0 Hz, 2H),7.67-7.72 (m, 1H), 7.53-7.60 (m, 1H), 7.28 (d, J = 6.0 Hz, 2H), 7.23 (m,1H), 7.17 (s, 1H), 4.40 (m, 1H), 4.23 (m, 1H), 3.51-3.55 (m, 3H), 3.24(m, 1H) and 1.93 (m, 4H) 91

49% 489.11 (M + H)⁺, 96.81% δ 10.49 (s, 1H), 8.61 (d, J = 5.60 Hz, 2H),7.95-7.98 (m, 1H), 7.81-7.89 (m, 2H), 7.59-7.65 (m, 1H), 7.41-7.44 (m,2H), 7.32 (d, J = 6.0 Hz, 3H), 3.54 (s, 3H) and 3.52 (s, 3H) 92

33% 433.31 (M + H)⁺, 99.88% δ 10.80 (s, 1H), 8.61 (d, J = 6.0 Hz, 2H),8.27 (s, 1H), 7.98 (d, J = 8.80 Hz, 1H), 7.80-7.84 (m, 2H), 7.57-7.64(m, 1H), 7.44 (s, 1H), 7.31-7.33 (m, 3H) and 5.41 (s, 2H) 93

82% 441.36 (M + H)⁺, 98.16% δ 8.59 (d, J = 5.60 Hz, 2H), 7.66-7.70 (m,1H), 7.52-7.59 (m, 1H), 7.27 (d, J = 6.0 Hz, 2H), 7.22 (m, 1H), 7.16 (s,1H), 4.22 (m, 1H), 4.06 (m, 1H), 3.86-3.94 (m, 2H), 3.65-3.74 (m, 2H),1.70 (m, 4H) and 1.20 (m, 4H) 94

57% 426.59 (M + H)⁺, 98.12% δ 8.59 (d, J = 6.0 Hz, 2H), 7.70-7.75 (m,1H), 7.53-7.60 (m, 1H), 7.28 (d, J = 4.80 Hz, 2H), 7.20 (m, 2H),4.50-4.81 (m, 2H), 4.34-4.44 (m, 1H), 3.96-4.06 (m, 1H), 3.87 (m, 1H),3.63-3.72 (m, 1H), 3.18- 3.21 (m, 1H), 3.0-3.09 (m, 1H) and 2.77- 2.86(m, 1H) 95

43% 515.03 (M + H)⁺, 98.41% δ 8.59 (m, 2H), 7.64-7.72 (m, 3H), 7.52-7.59 (m, 1H), 7.37-7.41 (m, 2H), 7.28 (m, 2H), 7.21 (m, 1H), 7.19 (s,1H), 7.12-7.16 (m, 1H), 4.73-4.76 (m, 2H), 4.41-4.51 (m, 2H), 3.60 (m,1H), 3.48 (m, 1H), 3.15 (m, 1H) and 1.66-1.80 (m, 4H) 96

67% 469.37 (M + H)⁺, 98.48% δ 8.59 (d, J = 6.0 Hz, 2H), 7.66-7.70 (m,1H), 7.52-7.59 (m, 1H), 7.27 (d, J = 6.0 Hz, 2H), 7.21 (m, 1H), 7.16 (s,1H), 4.05- 4.08 (m, 2H), 3.94-3.98 (m, 1H), 3.76- 3.88 (m, 2H),3.63-3.66 (m, 1H), 3.50 (m, 1H), 1.69 (m, 4H), 1.23-1.52 (m, 4H) and0.88 (t, J = 6.80 Hz, 3H) 97

34% 465.29 (M − H)⁺, 99.18% δ 8.93 (br s, 1H), 8.60 (d, J = 5.60 Hz,2H), 7.69-7.73 (m, 1H), 7.54-7.61 (m, 1H), 7.29 (d, J = 5.60 Hz, 2H),7.24 (m, 1H), 7.21 (s, 1H), 4.46 (m, 1H), 4.34 (m, 1H), 3.62 (m, 1H),3.29 (m, 1H), 2.85 (s, 3H), 1.82-1.88 (m, 2H) and 1.61-1.67 (m, 2H) 98

65% 550.40 (M + H)⁺, 95.71% δ 8.63 (m, 2H), 7.87-7.91 (m, 1H), 7.69-7.72 (m, 1H), 7.34-7.36 (m, 3H), 7.23- 7.26 (m, 3H), 7.15-7.17 (m, 1H),6.97- 7.01 (m, 1H), 4.70 (m, 2H), 4.42 (m, 1H), 3.54 (s, 2H), 3.37 (m,1H), 2.94 (m, 1H), 2.30-2.38 (m, 2H) and 1.71-1.79 (m, 2H) 99

43% 581.34 (M − H)⁺, 98.78% δ 8.82 (br s, 1H),8.63 (d, J = 5.60 Hz, 2H),7.85-7.89 (m, 1H), 7.67-7.69 (m, 1H), 7.30-7.35 (m, 3H), 7.22 (s, 1H),7.08-7.12 (m, 2H), 6.84-6.87 (m, 2H), 4.59 (s, 2H), 4.42-4.45 (m, 2H),3.87 (m, 1H), 3.54 (m, 1H), 2.20-2.36 (m, 2H) and 1.73-1.80 (m, 2H) 100

50% 599.40 (M + H)⁺, 96.20% δ 8.88 (br s, 1H), 8.64 (d, J = 4.40 Hz,2H), 7.84-7.88 (m, 1H), 7.67-7.70 (m, 1H), 7.25-7.36 (m, 6H), 6.78 (d, J= 8.80 Hz, 2H), 4.61 (br s, 2H), 4.44-4.49 (m, 2H), 3.84-3.90 (m, 1H),3.50-3.57 (m, 1H), 2.35-2.42 (m, 2H) and 1.71-1.81 (m, 2H) 101

68% 523.33 (M + H)⁺, 95.04% δ 8.63 (d, J = 6.0 Hz, 2H), 7.86-7.91 (m,1H), 7.71 (m, 1H), 7.29-7.36 (m, 7H), 7.22 (s, 1H), 5.04 (s, 2H),4.55-4.58 (m, 2H), 3.47-3.54 (m, 1H), 3.10-3.17 (m, 1H), 1.90-2.01 (m,2H) and 1.68-1.77 (m, 2H) 102

53% 537.35 (M + H)⁺, 95.01% δ 8.64 (d, J = 5.60 Hz, 2H), 7.78-7.91 (m,4H), 7.70-7.73 (m, 1H), 7.60-7.64 (m, 1H), 7.33-7.36 (m, 3H), 7.25 (s,1H), 4.66-4.76 (m, 2H), 3.54-3.57 (m, 1H), 3.14-3.21 (m, 1H), 2.29-2.36(m, 2H) and 1.72-1.80 (m, 2H) 103

31% 571.31 (M + H)⁺, 99.71% δ 8.64 (d, J = 5.20 Hz, 2H), 7.85-7.91 (m,4H), 7.70-7.73 (m, 1H), 7.33-7.36 (m, 3H), 7.24 (s, 1H), 4.66-4.76 (m,2H), 3.49-3.55 (m, 1H), 3.12-3.19 (m, 1H), 2.30-2.37 (m, 2H) and1.74-1.83 (m, 2H) 104

67% 536.36 (M + H)⁺, 96.92% δ 8.64-8.65 (m, 2H), 7.70-7.97 (m, 2H),7.18-7.42 (m, 8H), 5.13-5.52 (m, 1H), 3.48-5.0 (m, 4H), 3.30 (m, 1H) and2.79- 2.91 (m, 3H) 105

70% 565.37 (M + H)⁺, 94.01% δ 8.63 (d, J = 6.0 Hz, 2H), 7.87-7.91 (m,1H), 7.69-7.72 (m, 1H), 7.34-7.36 (m, 4H), 7.24 (s, 1H), 7.13-7.16 (m,1H), 7.04-7.08 (m, 2H), 4.70-4.74 (m, 2H), 4.53-4.59 (m, 1H), 3.37 (m,1H), 3.30 (s, 3H), 2.94-3.0 (m, 1H), 2.30-2.38 (m, 2H) and 1.77-1.86 (m,2H) 106

86% 580.35 (M + H)⁺, 95.40% δ 8.62 (m, 2H), 7.85-7.91 (m, 1H), 7.59-7.71 (m, 1H), 7.24-7.40 (m, 8H), 7.07- 7.14 (m, 1H), 5.01 (m, 1H),4.57-4.62 (m, 2H), 4.43 (m, 1H), 3.98 (m, 1H), 3.59 (m, 1H), 3.03 (m,1H), 2.72 (m, 1H), 1.85- 1.94 (m, 1H), 1.56-1.77 (m, 2H) and 1.23 (m,1H) 107

76% 509.31 (M + H)⁺, 95.64% δ 8.63 (d, J = 6.0 Hz, 2H), 7.88 (m, 1H),7.70-7.72 (m, 1H), 7.32-7.34 (m, 3H), 7.19 (s, 1H), 3.94 (m, 2H), 3.74(m, 2H), 3.35 (m, 4H) and 2.09 (m, 4H) 108

31% 536.36 (M + H)⁺, 95.15% δ 8.63 (d, J = 5.60 Hz, 2H), 7.89 (t, J =8.40 Hz, 1H), 7.67-7.73 (m, 3H), 7.35 (m, 5H), 7.21 (s, 1H), 4.47-4.54(m, 2H), 3.39-3.52 (m, 2H), 3.13-3.19 (m, 1H), 2.18-2.25 (m, 2H) and1.18-1.23 (m, 2H) 109

57% 507.27 (M + H)⁺, 97.62% δ 10.56 (s, 1H), 8.64-8.65 (m, 2H), 7.94-7.90 (m, 2H), 7.85 (m, 1H), 7.62 (dd, J = 8.80 & 2.00 Hz, 1H) and7.39-7.43 (m, 5H) 110

77% 510.23 (M − H)⁺, 97.05% δ 10.35 (s, 1H), 8.65 (d, J = 6.00 Hz, 2H),7.93 (d, J = 8.00 Hz, 1H), 7.86 (m, 1H), 7.59 (d, J = 2.40 Hz, 1H), 7.54(dd, J = 8.80 & 2.40 Hz, 1H), 7.38-7.41 (m, 4H), 7.16 (d, J = 8.8 Hz,1H), 4.66 (s, 2H) and 3.28 (s, 3H) 111

58% 504.25 (M − H)⁺, 98.75% δ 8.62-8.63 (m, 2H), 8.40 (s, 1H), 7.89 (t,J = 8.00 Hz, 1H), 7.72 (m, 1H), 7.33-7.35 (m, 3H), 7.20 (s, 1H),4.35-4.39 (m, 1H), 4.21-4.24 (m, 1H), 3.69 (m, 4H), 3.30 (m, 1H) and2.08-2.11 (m, 3H) 112

54% 539.14 (M + H)⁺, 98.59% δ 10.43 (s, 1H), 8.65 (d, J = 6.0 Hz, 2H),7.91-7.96 (m, 2H), 7.85 (d, J = 8.0 Hz, 2H), 7.38-7.45 (m, 5H), 3.55 (s,3H) and 3.54 (s, 3H) 113

38% 481.20 (M − H)⁺, 99.50% δ 10.80 (s, 1H), 8.65 (d, J = 6.0 Hz, 2H),8.27 (s, 1H), 7.92-7.98 (m, 2H), 7.84-7.89 (m, 2H), 7.48 (s, 1H),7.39-7.43 (m, 3H) and 5.42 (s, 2H) 114

67% 491.36 (M + H)⁺, 99.52% δ 8.62 (d, J = 6.00 Hz, 2H), 7.89 (d, J =8.40 Hz, 1H), 7.71 (m, 1H), 7.32-7.35 (m, 3H), 7.19 (s, 1H), 4.19-4.22(m, 1H), 4.05-4.10 (m, 1H), 3.76-3.95 (m, 4H), 3.40-3.46 (m, 1H),1.69-1.70 (m, 4H) and 1.19-1.22 (m, 3H) 115

81% 476.11 (M + H)⁺, 99.38% δ 8.63 (d, J = 5.60 Hz, 2H), 7.89 (t, J =8.00 Hz, 1H), 7.76 (d, J = 10.40 Hz, 1H), 7.35 (br s, 3H), 7.24 (s, 1H),4.51-4.76 (m, 2H), 4.34-4.54 (m, 1H), 3.88-4.07 (m, 2H), 3.64-3.73 (m,1H), 3.08-3.11 (m, 1H), 3.19-3.22 (m, 1H) and 2.82-2.87 (m, 1H) 116

57% 303.75 (M + H)⁺, 99.72% δ 8.62 (d, J = 6.40 Hz, 2H), 7.89 (t, J =8.40 Hz, 1H), 7.65-7.72 (m, 3H), 7.35- 7.41 (m, 5H), 7.22 (s, 1H), 7.15(t, J = 7.20 Hz, 1H), 4.71-4.76 (m, 2H), 4.42- 4.47 (m, 2H), 3.61-3.63(m, 1H), 3.47- 3.53 (m, 1H), 3.16-3.17 (m, 1H) and 1.68- 1.79 (m, 4H)117

39% 519.17 (M + H)⁺, 99.31% δ 8.62 (d, J = 5.20 Hz, 2H), 7.89 (t, J =8.4 Hz, 1H), 7.70 (d, J = 10.8 Hz, 1H), 7.32- 7.35 (m, 3H), 7.19 (s,1H), 4.07-4.09 (m, 2H), 3.76-3.96 (m, 3H), 3.62-3.65 (m, 1H), 3.50-3.51(m, 1H), 1.74 (br s, 4H), 1.23-1.69 (m, 4H) and 0.88-0.92 (m, 3H) 118

67% 517.13 (M + H)⁺, 99.26% δ 8.94 (s, 1H), 8.63 (d, J = 4.80 Hz, 2H),7.89 (t, J = 7.6 Hz, 1H), 7.72 (d, J = 12.0 Hz, 1H), 7.34-7.35 (m, 3H),7.23 (s, 1H), 4.31-4.43 (m, 2H), 3.58-3.64 (m, 1H), 3.29 (m, 1H), 2.84(s, 3H), 1.85-1.89 (m, 2H) and 1.64-1.70 (m, 2H) 119

29% 533.35 (M + H)⁺, 96.97% δ 8.84 (s, 1H), 8.63 (m, 2H), 8.04-8.10 (m,2H), 7.38 (d, J = 6.0 Hz, 2H), 7.23- 7.28 (m, 3H), 7.17 (d, J = 8.40 Hz,1H), 6.99 (t, J = 7.2 Hz, 1H), 4.72 (m, 2H), 4.40-4.46 (m, 1H), 3.54 (s,2H), 3.35-3.41 (m, 1H), 2.92-2.98 (m, 1H), 2.33-2.40 (m, 1H), 1.71-1.80(m, 2H) and 1.07-1.11 (m, 1H) 120

38% 564.37 (M − H)⁺, 98.73% δ 8.82 (br s, 2H), 8.63 (d, J = 6.0 Hz, 2H),8.03 (s, 2H), 7.37 (d, J = 6.0 Hz, 2H), 7.26 (s, 1H), 7.10 (t, J = 8.80Hz, 2H), 6.84 (m, 2H), 4.65 (s, 2H), 4.59-4.60 (m, 2H), 3.86-3.92 (m,1H), 3.51-3.58 (m, 1H), 3.35-3.39 (m, 1H), 2.19-2.29 (m, 2H) and1.07-1.11 (m, 1H) 121

46% 582.41 (M + H)⁺, 96.72% δ 8.88 (br s, 2H), 8.83 (s, 1H), 8.64 (d, J= 5.60 Hz, 2H), 8.03 (br s, 2H), 7.38 (d, J = 5.60 Hz, 2H), 7.24-7.29(m, 3H), 6.78 (d, J = 8.80 Hz, 2H), 4.61 (br s, 2H), 4.51 (m, 2H),3.86-3.91 (m, 1H), 3.51-3.57 (m, 1H), 2.41 (m, 2H) and 1.72-1.81 (m, 2H)122

30% 506.36 (M + H)⁺, 98.17% δ 8.84 (br s, 1H), 8.64 (d, J = 6.0 Hz, 2H),8.03-8.09 (m, 2H), 7.37-7.39 (m, 2H), 7.29-7.33 (m, 5H), 5.05 (s, 2H),4.58 (m, 2H), 3.48-3.55 (m, 1H), 3.12-3.15 (m, 1H), 1.90-1.99 (m, 2H)and 1.69-1.78 (m, 2H) 123

41% 520.34 (M + H)⁺, 95.11% δ 8.86 (br s, 1H), 8.64 (d, J = 6.0 Hz, 2H),8.04-8.10 (m, 2H), 7.77-7.87 (m, 3H), 7.62 (t, J = 7.20 Hz, 1H), 7.38(d, J = 6.0 Hz, 2H), 7.29 (s, 1H), 4.67-4.76 (m, 2H), 3.56 (m, 1H), 3.19(m, 1H) and 2.25-2.37 (m, 4H) 124

70% 554.30 (M + H)⁺, 97.55% δ 8.85 (br s, 1H), 8.64 (d, J = 6.0 Hz, 2H),8.04-8.10 (m, 2H), 7.84-7.92 (m, 3H), 7.38 (dd, J = 4.40 & 2.0 Hz, 2H),7.28 (s, 1H), 4.67-4.77 (m, 2H), 3.53 (m, 1H), 3.16 (m, 1H), 2.69 (m,1H) and 2.49-2.50 (m, 3H) 125

46% 519.37 (M + H)⁺, 98.55% δ 8.83-8.95 (distorted s, 1H), 8.64 (m, 2H),8.05-8.16 (m, 2H), 7.23-7.41 (m, 7H), 5.00-5.17 (m, 1H), 4.54-4.92 (m,3H), 3.97-4.44 (m, 1H), 3.49-3.56 (m, 1H) and 2.67-2.89 (m, 3H) 126

59% 548.35 (M + H)⁺, 95.06% δ 8.84 (s, 1H), 8.63 (d, J = 5.6 Hz, 2H),8.04-8.09 (m, 2H), 7.38 (d, J = 5.6 Hz, 2H), 7.28-7.32 (m, 2H),7.14-7.16 (m, 1H), 7.06-7.08 (m, 2H), 4.73 (m, 2H), 4.54-4.60 (m, 1H),3.43 (m, 1H), 3.31 (s, 3H), 2.95-3.04 (m, 1H), 2.33-2.39 (m, 2H) and1.78-1.86 (m, 2H) 127

46% 563.38 (M + H)⁺, 98.89% δ 8.76-8.83 (two signals due to rotationalisomer, 1H), 8.62 (br s, 2H), 7.98-8.05 (m, 2H), 7.32-7.40 (m, 7H),7.11-7.17 (two signals due to rotational isomer, 1H), 4.99-5.03 (m, 1H),4.53-4.62 (m, 2H), 4.40-4.43 (m, 1H), 3.97-4.01 (m, 1H), 3.60-3.62 (m,1H), 3.06-3.09 (m, 1H), 2.67-2.73 (m, 1H), 1.83-1.95 (m, 1H), 1.55-1.78(m, 2H) and 1.24-1.30 (m, 1H) 128

88% 492.30 (M + H)⁺, 97.31% δ 8.83 (s, 1H), 8.63 (d, J = 6.0 Hz, 2H),8.06-8.07 (m, 2H), 7.36 (d, J = 6.4 Hz, 2H), 7.23 (s, 1H), 3.94 (m, 2H),3.74 (m, 2H), 3.33-3.35 (m, 4H) and 2.10 (m, 4H) 129

71% 452.36 (M + H)⁺, 98.30% δ 9.18 (s, 1H), 8.73 (d, J = 2.8 Hz, 1H),8.58 (d, J = 5.6 Hz, 2H), 8.42 (s, 1H), 7.68-7.72 (m, 2H), 7.33-7.38 (m,4H), 7.21 (s, 1H), 4.50 (m, 2H), 3.37-3.54 (m, 2H), 3.15-3.21 (m, 1H),2.20-2.23 (m, 2H) and 1.82-1.91 (m, 2H) 130

46% 421.24 (M − H)⁺, 99.49% δ 10.60 (s, 1H), 9.33 (s, 1H), 8.78 (d, J =2.4 Hz, 1H), 8.60 (d, J = 6.0 Hz, 2H), 8.46-8.47 (m, 1H), 7.95 (d, J =2.0 Hz, 1H), 7.61-7.64 (m, 1H) and 7.39-7.44 (m, 4H) 131

93% 426.26 (M − H)⁺, 95.02% δ 10.39 (s, 1H), 9.35 (s, 1H), 8.77 (d, J =2.4 Hz, 1H), 8.60 (d, J = 6.0 Hz, 2H), 8.45 (s, 1H), 7.55-7.60 (m, 2H),7.40-7.41 (m, 3H), 7.17 (d, J = 8.8 Hz, 1H), 4.67 (s, 2H) and 3.33 (s,3H) 132

29% 422.30 (M + H)⁺, 98.86% δ 9.17 (s, 1H), 8.94 (br s, 1H), 8.73 (d, J= 2.4 Hz, 1H), 8.57-8.59 (m, 2H), 8.41-8.42 (m, 1H), 7.35-7.37 (m, 2H),7.19 (s, 1H), 4.22-4.38 (m, 2H), 3.55-3.60 (m, 3H), 3.28 (m, 1H) and1.90-1.97 (m, 4H) 133

31% 455.11 (M + H)⁺, 98.49% δ 10.55 (s, 1H), 9.36 (s, 1H), 8.79 (d, J =2.40 Hz, 1H), 8.61 (d, J = 5.60 Hz, 2H), 8.47 (br s, 1H), 8.00 (br s,1H), 7.85-7.89 (m, 1H), 7.40-7.47 (m, 4H), 3.55 (s, 3H) and 3.54 (s, 3H)134

31% 399.10 (M + H)⁺, 92.75% δ 10.85 (s, 1H), 9.36 (s, 1H), 8.79 (d, J =2.40 Hz, 1H), 8.60 (d, J = 5.60 Hz, 2H), 8.47 (br s, 1H), 8.28 (s, 1H),7.98 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.40 Hz, 1H), 7.47 (s, 1H), 7.41(d, J = 6.0 Hz, 2H) and 5.42 (s, 2H) 135

44% 407.37 (M + H)⁺, 99.68% δ 9.16 (s, 1H), 8.73 (d, 2.8 Hz, 1H),8.57-8.58 (m, 2H), 8.40-8.41 (m, 1H), 7.35-7.36 (m, 2H), 7.19 (s, 1H),4.21-4.25 (m, 1H), 4.05-4.10 (m, 1H), 3.63-3.98 (m, 4H), 3.40-3.46 (m,1H), 1.72 (m, 4H) and 1.20 (m, 3H) 136

37% 392.29 (M + H)⁺, 97.02% δ 9.23 (d, J = 9.2 Hz, 1H), 8.74 (d, J = 2.4Hz, 1H), 8.58 (d, J = 6.0 Hz, 2H), 8.41 (s, 1H), 7.36 (br s, 2H), 7.23(d, J = 2.4 Hz, 1H), 4.52-4.78 (m, 2H), 4.37-4.43 (m, 1H), 3.90-4.08 (m,2H), 3.66-3.74 (m, 1H), 3.12-3.33 (m, 2H) and 2.83-2.89 (m, 1H) 137

79% 481.39 (M + H)⁺, 97.37% δ 9.17 (s, 1H), 8.73 (d, J = 2.4 Hz, 1H),8.57-8.59 (m, 2H), 8.41-8.42 (m, 1H), 7.66 (d, J = 8.0 Hz, 2H),7.36-7.41 (m, 4H), 7.21 (s, 1H), 7.15 (t, J = 7.2 Hz, 1H), 4.17-4.79 (m,2H), 4.44-4.46 (m, 2H), 3.63 (t, J = 9.2 Hz, 1H), 3.49-3.55 (m, 1H),3.18-3.22 (m, 1H) and 1.70-1.75 (m, 4H) 138

33% 435.38 (M + H)⁺, 99.02% δ 9.16 (s, 1H), 8.72 (d, J = 2.4 Hz, 1H),8.58 (d, J = 2.4 Hz, 2H), 8.41 (s, 1H), 7.36 (d, J = 5.6 Hz, 2H), 7.19(s, 1H), 4.05-4.09 (m, 2H), 3.66-3.96 (m, 4H), 3.49-3.51 (m, 1H), 1.71(m, 4H), 1.23-1.57 (m, 4H) and 0.90 (t, J = 6.8 Hz, 3H) 139

37% 431.28 (M − H)⁺, 99.81% δ 9.16 (s, 1H), 8.93 (s, 1H), 8.73 (d, J =2.4 Hz, 1H), 8.58 (d, J = 6.0 Hz, 2H), 8.42 (s, 1H), 7.36 (d, J = 5.6Hz, 2H), 7.22 (s, 1H), 4.31-4.43 (m, 2H), 3.61-3.72 (m, 1H), 2.85 (s,3H), 1.83-1.94 (m, 2H), 1.69 (m, 2H) and 1.23-1.27 (m, 1H) 140

36% 531.32 (M − H)⁺, 99.38% δ 8.84 (br s, 1H), 8.60 (d, J = 6.4 Hz, 2H),7.51-7.55 (m, 2H), 7.31-7.32 (m, 2H), 7.20-7.24 (m, 3H), 6.74-6.78 (m,3H), 4.62 (s, 2H), 4.47-4.53 (m, 2H), 3.83-3.89 (m, 1H), 3.49-3.56 (m,1H) and 1.69-1.88 (m, 4H) 141

28% 517.31 (M − H)⁺, 98.75% δ 8.60 (d, J = 6.0 Hz, 2H), 7.55-7.58 (m,2H), 7.32 (d, J = 6.0 Hz, 2H), 7.23-7.24 (m, 2H), 6.97 (m, 3H),4.69-4.76 (m, 2H), 4.47-4.53 (m, 1H), 3.29-3.60 (m, 2H), 2.92-2.98 (m,1H), 2.29-2.36 (m, 2H) and 1.75-1.81 (m, 2H) 142

47% 445.30 (M + H)⁺, 99.52% δ 8.59-8.60 (m, 2H), 7.53-7.57 (m, 2H),7.29-7.31 (m, 2H), 7.19 (s, 1H), 3.92 (m, 6H), 3.71 (m, 2H) and1.75-1.88 (m, 4H) 175

29% 555.43 (M + H)⁺, 99.51% δ 11.25 (br s, 1H), 8.60 (d, J = 6.0 Hz,2H), 7.54-7.58 (m, 2H), 7.32 (d, J = 6.0 Hz, 2H), 7.23 (s, 1H), 7.0-7.07(m, 1H), 6.77-6.80 (m, 1H), 4.78-4.81 (m, 1H), 4.66-4.69 (m, 2H), 3.30(m, 1H), 2.92- 2.98 (m, 1H), 2.13-2.19 (m, 2H) and 1.84- 1.90 (m, 2H)176

22% 587.40 (M + H)⁺, 99.83% δ 11.26 (br s, 1H), 8.61 (d, J = 6.0 Hz,2H), 7.54-7.58 (m, 2H), 7.45-7.47 (m, 1H), 7.35-7.37 (m, 1H), 7.32 (d, J= 6.0 Hz, 2H), 7.21-7.24 (m, 2H), 4.70-4.78 (m, 2H), 4.53-4.59 (m, 1H),3.30 (m, 1H), 2.92-2.98 (m, 1H), 2.25-2.35 (m, 2H) and 1.79-1.90 (m, 2H)179

10% 649.53 (M + H)⁺, 96.93% δ 8.90 (s, 1H), 8.60-8.64 (m, 2H), 7.85 (t,J = 7.2 Hz, 1H), 7.69 (d, J = 10.8 Hz, 1H), 7.30-7.36 (m, 3H), 7.20-7.25(m, 3H), 6.82 (d, J = 8.0 Hz, 2H), 6.54 (s, 1H), 4.63 (s, 2H), 4.44-4.51(m, 2H), 3.84-3.86 (m, 1H), 3.51-3.57 (m, 1H), 2.59 (m, 1H) and1.71-1.87 (m, 2H)

In another embodiment, compounds of the disclosure are made according toScheme F.

Preparation of ethyl 2,4-dioxo-4-(pyridin-4-yl)butanoate (F-2)

A solution of 4-acetyl pyridine (10.0 g, 82.55 mmol) in diethyl ether(160 mL) was cooled to −78° C. followed by addition of LiHMDS (15.16 g,90.80 mmol). The resulting reaction mixture was stirred at −78° C. for45 min followed by dropwise addition of diethyl oxalate (13.5 mL, 98.92mmol) in about 30 min. The reaction mixture was then left to stir atroom temperature for 16 h. After completion of the reaction (TLC and MSmonitoring), the solution was then cooled 0° C. and the resultingprecipitate was filtered to get the desired product as an off-whitesolid (18.0 g, 98%), which was carried forward to the next step withoutpurification. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.66 (d, J=4.80 Hz, 2H), 7.70(d, J=5.20 Hz, 2H), 6.43 (s, 1H), 4.15 (q, J=7.20 Hz, 2H) and 1.25 (t,J=7.20 Hz, 3H).

General Procedure for the Preparation of Compounds F-3a-j:

To an ice-cold solution of ethyl 2,4-dioxo-4-(pyridin-4-yl)butanoate F-2(1.0 eq) in IPA was added a respective hydrazine (1.10 eq) and TFA (2.0eq). The resulting reaction mixture was warmed up to room temperatureand then stirred at 90° C. for 4-5 h. After completion of the reaction(TLC monitoring), the solvent was evaporated and the residue was dilutedwith water and extracted with ethyl acetate (3 times). The combinedorganics were washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated. The crude was purified over silica gel(100-200 Mesh, 10-15% EtOAc-hexane) to get the desired product.

Ethyl5-(pyridin-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylate(F-3a)

¹H-NMR (400 MHz, CDCl₃): δ 8.61 (d, J=6.0 Hz, 2H), 7.66 (d, J=8.4 Hz,2H), 7.47 (d, J=8.4 Hz, 2H), 7.17 (s, 1H), 7.11 (m, 2H), 4.44 (q, J=7.20Hz, 2H) and 1.41 (t, J=7.20 Hz, 3H). LCMS: 362.21 (M+H)⁺, 99.95%. Yield:50%.

Ethyl5-(pyridin-4-yl)-1-(3-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylate(F-3b)

¹H-NMR (400 MHz, CDCl₃): δ 8.60 (d, J=6.0 Hz, 2H), 7.73 (s, 1H), 7.67(d, J=8.0 Hz, 1H), 7.49 (m, 1H), 7.35 (m, 1H), 7.23 (s, 1H), 7.14 (m,2H), 4.29 (q, J=7.20 Hz, 2H) and 1.42 (t, J=7.20 Hz, 3H). LCMS: 362.22(M+H)⁺, 91.70%. Yield: 62%.

Ethyl 1-(3,4-difluorophenyl)-5-(pyridin-4-yl)-1H-pyrazole-3-carboxylate(F-3c)

¹H-NMR (400 MHz, CDCl₃): δ 8.61 (d, J=6.0 Hz, 2H), 7.31 (m, 1H), 7.30(s, 1H), 7.19 (m, 1H), 7.04 (m, 2H), 7.01 (m, 1H), 4.43 (q, J=7.20 Hz,2H) and 1.39 (t, J=7.20 Hz, 3H). LCMS: 330.14 (M+H)⁺, 93.07%. Yield:55%.

Ethyl 1-(2,4-difluorophenyl)-5-(pyridin-4-yl)-1H-pyrazole-3-carboxylate(F-3d)

¹H-NMR (400 MHz, CDCl₃): δ 8.62 (d, J=6.4 Hz, 2H), 7.82 (m, 1H), 7.55(m, 1H), 7.53 (s, 1H), 7.34 (m, 3H), 4.32 (q, J=7.20 Hz, 2H) and 1.30(t, J=7.20 Hz, 3H). LCMS: 330.21 (M+H)+, 91.46%. Yield: 65%.

Ethyl1-(benzo[d][1,3]dioxol-5-yl)-5-(pyridin-4-yl)-1H-pyrazole-3-carboxylate(F-3e)

¹H-NMR (400 MHz, CDCl₃): δ 8.57 (d, J=6.0 Hz, 2H), 7.10 (m, 3H), 6.81(s, 1H), 6.72 (m, 2H), 6.04 (s, 2H), 4.42 (q, J=7.20 Hz, 2H) and 1.40(t, J=7.20 Hz, 3H). LCMS: 338.20 (M+H)+, 77.49%. Yield: 20%.

Ethyl1-(3,5-bis(trifluoromethyl)phenyl)-5-(pyridin-4-yl)-1H-pyrazole-3-carboxylate(F-3f)

¹H-NMR (400 MHz, CDCl₃): δ 8.56 (dd, J=1.6 & 4.40 Hz, 2H), 7.90 (s, 1H),7.82 (s, 2H), 7.20 (s, 1H), 7.12 (dd, J=1.6 & 4.40 Hz, 2H), 4.45 (q,J=7.20 Hz, 2H) and 1.42 (t, J=7.20 Hz, 3H). LCMS: 430.26 (M+H)⁺, 93.03%.Yield: 32%.

Ethyl1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-4-yl)-1H-pyrazole-3-carboxylate(F-3g)

¹H-NMR (400 MHz, CDCl₃): δ 8.68 (dd, J=1.6 & 4.40 Hz, 2H), 7.60 (m, 1H),7.36 (m, 1H), 7.14 (m, 4H), 4.44 (q, J=7.20 Hz, 2H) and 1.39 (t, J=6.80Hz, 3H). MS: 380.0 (M+H)⁺. Yield: 45%.

Ethyl5-(pyridin-4-yl)-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-3-carboxylate(F-3h)

¹H-NMR (400 MHz, CDCl₃): δ 8.67 (m, 3H), 7.92 (dd, J=2.0 & 8.40 Hz, 1H),7.76 (s, 1H), 7.18 (m, 3H), 4.45 (q, J=7.20 Hz, 2H) and 1.42 (t, J=6.80Hz, 3H). LCMS: 362.89 (M+H)⁺, 98.45%. Yield: 50%.

Ethyl 1-(pyrazin-2-yl)-5-(pyridin-4-yl)-1H-pyrazole-3-carboxylate (F-3i)

¹H-NMR (400 MHz, CDCl₃): δ 9.21 (d, J=1.20 Hz, 1H), 8.62 (m, 2H), 8.60(m, 1H), 8.23 (dd, J=1.2 & 2.40 Hz, 1H), 7.17 (d, J=6.0 Hz, 2H), 7.14(s, 1H), 4.45 (q, J=7.20 Hz, 2H) and 1.42 (t, J=6.80 Hz, 3H). LCMS:296.18 (M+H)⁺, 96.22%. Yield: 30%.

Ethyl 1-phenyl-5-(pyridin-4-yl)-1H-pyrazole-3-carboxylate (F-3j)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.55 (d, J=6.0 Hz, 2H), 7.51 (m, 3H), 7.38(m, 3H), 7.24 (m, 2H), 4.35 (q, J=7.20 Hz, 2H) and 1.32 (t, J=7.20 Hz,3H). Yield: 33%.

General Procedure for the Preparation of Compounds F-4a-j:

To an ice-cold solution of compound (F-3a-j) (1.0 eq) in EtOH was addeddropwise an aqueous solution of sodium hydroxide (3.0 eq). The resultingsolution was stirred at room temperature for 4 h. After completion ofthe reaction (TLC monitoring), the solvent was evaporated, added H₂O tothe residue followed by extraction with EtOAc (2×100 mL). The organiclayer was discarded and the pH of the aqueous layer was adjusted to ˜6by adding 1N HCl. The resulting precipitate was filtered and dried undervacuum to get the desired product (60-80%) as a white solid.

5-(Pyridin-4-yl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylicAcid (F-4a)

¹H-NMR (400 MHz, DMSO-d₆): δ 12.84 (br s, 1H), 8.58 (d, J=5.60 Hz, 2H),7.87 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 7.28 (m, 3H). LCMS:334.13 (M+H)⁺, 97.98%. Yield: 95%.

5-(Pyridin-4-yl)-1-(3-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylicAcid (F-4b)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.58 (d, J=6.00 Hz, 2H), 7.85 (d, J=8.0 Hz,1H), 7.79 (s, 1H), 7.69 (m, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.31 (s, 1H),7.26 (m, 2H). LCMS: 334.13 (M+H)+, 98.62%. Yield: 94%.

1-(3,4-Difluorophenyl)-5-(pyridin-4-yl)-1H-pyrazole-3-carboxylic Acid(F-4c)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.17 (br s, 1H), 8.57 (d, J=5.60 Hz, 2H),7.69 (m, 1H), 7.54 (m, 1H), 7.22 (m, 4H). MS: 302.18 (M+H)⁺. Yield: 78%.

1-(2,4-Difluorophenyl)-5-(pyridin-4-yl)-1H-pyrazole-3-carboxylic Acid(F-4d)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.20 (br s, 1H), 8.56 (d, J=5.60 Hz, 2H),7.80 (m, 1H), 7.51 (m, 1H), 7.32 (m, 2H), 7.25 (m, 2H). LCMS: 301.80(M+H)⁺, 98.31%. Yield: 85%.

1-(Benzo[d][1,3]dioxol-5-yl)-5-(pyridin-4-yl)-1H-pyrazole-3-carboxylicAcid (F-4e)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.12 (br s, 1H), 8.56 (m, 2H), 7.25-7.27(m, 3H), 7.04 (m, 1H), 6.97 (d, J=8.0 Hz, 1H), 6.79-6.81 (m, 1H) and6.14 (s, 2H). LCMS: 310.10 (M+H)⁺, 99.56%. Yield: 82%.

1-(3,5-Bis(trifluoromethyl)phenyl)-5-(pyridin-4-yl)-1H-pyrazole-3-carboxylicAcid (F-4f)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.17 (br s, 1H), 8.59 (d, J=6.0 Hz, 2H),8.26 (s, 1H), 8.07 (s, 2H), 7.32 (m, 3H). LCMS: 402.15 (M+H)⁺, 91.73%.Yield: 94%.

1-(3-Fluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-4-yl)-1H-pyrazole-3-carboxylicAcid (F-4g)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.60 (d, J=5.6 Hz, 2H), 7.88 (m, 1H), 7.67(s, 1H), 7.32 (m, 4H). LCMS: 352.17 (M+H)⁺, 98.60%. Yield: 92%.

5-(Pyridin-4-yl)-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (F-4h)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.07 (br s, 1H), 8.81 (s, 1H), 8.60 (d,J=6.0 Hz, 2H), 8.05 (m, 2H), 7.34 (m, 3H). LCMS: 335.13 (M+H)⁺, 97.97%.Yield: 75%.

1-(Pyrazin-2-yl)-5-(pyridin-4-yl)-1H-pyrazole-3-carboxylic Acid (F-4i)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.40 (br s, 1H), 9.15 (s, 1H), 8.75 (d,J=6.4 Hz, 1H), 8.56 (m, 2H), 8.43 (s, 1H), 7.33 (s, 3H). LCMS: 268.17(M+H)⁺, 99.0%. Yield: 74%.

1-Phenyl-5-(pyridin-4-yl)-1H-pyrazole-3-carboxylic Acid (F-4j)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.11 (br s, 1H), 8.55 (d, J=5.60 Hz, 2H),7.50 (m, 3H), 7.38 (m, 2H), 7.31 (s, 1H) and 7.23 (d, J=6.0 Hz, 2H).Yield: 61%.

General Procedure for the Preparation of Final Compounds (F-5):

To an ice-cold solution of carboxylic acids F-4(a-j) (1.0 eq), in DMF(2.0 mL) was added DIPEA (3.0 eq) and HATU (1.50 eq). The resultingmixture was stirred under nitrogen atmosphere at 0° C. for 15 minfollowed by addition of the respective amine (1.20 eq). The reactionmixture was then stirred at room temperature for 16 h. After thecompletion of the reaction (TLC monitoring), the solution was dilutedwith ice-cold water (30 mL) followed by extraction with EtOAc (3×50 mL).The combined organics were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The cruderesidue was purified via prep-TLC using the solvent systems 3-5%MeOH-DCM. The final step was performed on 75-100 mg scale.

Amines used in the preparation of the final compounds illustrated inTable 6 according to Scheme F are commercially available or can besynthesized by one of ordinary skill.

TABLE 6 Additional compounds of the disclosure prepared according thegeneral method disclosed in Scheme F. Cpd. Yield NMR data (DMSO-d₆, 400MHz), unless ID Structure (%) LCMS otherwise specified 143

43% 547.16 (M + H)⁺, 96.32% δ 8.84 (br s, 1H), 8.61 (d, J = 6.0 Hz, 2H),7.85 (d, J = 8.40 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 6.0Hz, 2H), 7.19- 7.23 (m, 3H), 6.73-6.78 (m, 3H), 4.61 (s, 2H), 4.51 (t, J= 13.20 Hz, 2H), 3.88 (t, J = 13.20 Hz, 1H), 3.54 (t, J = 12.40 Hz, 1H),2.60 (m, 2H) and 1.71-1.80 (m, 2H) 144

58% 533.16 (M + H)⁺, 95.43% δ 10.86 (br s, 1H), 8.61 (d, J = 6.0 Hz,2H), 7.87 (d, J = 8.80 Hz, 2H), 7.61 (d, J = 8.40 Hz, 2H), 7.32 (d, J =5.60 Hz, 2H), 7.23 (m, 2H), 6.97 (m, 3H), 4.74 (t, J = 15.20 Hz, 2H),4.51 (m, 1H), 3.30 (m, 1H), 2.95 (m, 1H), 2.26-2.37 (m, 2H) and1.76-1.85 (m, 2H) 145

60% 459.09 (M + H)⁺, 95.06% δ 8.60 (d, J = 6.0 Hz, 2H), 7.87 (d, J =8.40 Hz, 2H), 7.60 (d, J = 8.40 Hz, 2H), 7.30 (d, J = 6.0 Hz, 2H), 7.18(s, 1H), 3.92 (br s, 6H), 3.71 (m, 2H), and 1.68 (t, J = 5.20 Hz, 4H)146

49% 547.23 (M + H)⁺, 92.28% δ 8.83 (br s, 1H), 8.59 (d, J = 5.60 Hz,2H), 7.82 (d, J = 7.20 Hz, 1H), 7.75 (s, 1H), 7.63-7.70 (m, 2H), 7.29(d, J = 6.0 Hz, 2H), 7.19-7.22 (m, 3H), 6.73-6.78 (m, 3H), 4.61 (s, 2H),4.51 (m, 2H), 3.86 (t, J = 6.0 Hz, 1H), 3.53 (t, J = 13.20 Hz, 1H), 2.59(m, 2H) and 1.70-1.80 (m, 2H) 147

57% 533.16 (M + H)⁺, 99.17% δ 10.86 (br s, 1H), 8.59 (d, J = 6.0 Hz,2H), 7.84 (d, J = 7.20 Hz, 1H), 7.76 (s, 1H), 7.66-7.71 (m, 2H), 7.30(d, J = 6.0 Hz, 2H), 7.23-7.24 (m, 2H), 6.97-6.99 (m, 3H), 4.72 (m, 2H),4.50 (m, 1H), 3.36 (m, 1H), 2.95 (m, 1H), 2.29-2.36 (m, 2H) and1.76-1.85 (m, 2H) 148

58% 459.11 (M + H)⁺, 97.12% δ 8.59 (d, J = 6.0 Hz, 2H), 7.85 (d, J =7.60 Hz, 1H), 7.75 (s, 1H), 7.64-7.73 (m, 2H), 7.28 (d, J = 6.0 Hz, 2H),7.18 (s, 1H), 3.92 (br s, 6H), 3.71 (m, 2H), and 1.68 (t, J = 5.20 Hz,4H) 149

35% 515.34 (M +H)⁺, 95.94% CDCl₃: δ 8.59 (d, J = 5.60 Hz, 2H), 7.12-7.28 (m, 6H), 7.06 (s, 1H), 6.97 (m, 1H), 6.90 (m, 1H), 6.82 (d, J = 8.0Hz, 2H), 6.13 (br s, 1H), 4.76-4.78 (m, 4H), 4.03 (m, 1H), 3.68 (m, 1H),2.63-2.72 (m, 2H) and 1.80-2.0 (m, 2H) 150

36% 501.30 (M + H)⁺ 99.02% δ 10.86 (br s, 1H), 8.59 (d, J = 6.0 Hz, 2H),7.70-7.72 (m, 1H), 7.52-7.59 (m, 1H), 7.29 (d, J = 6.0 Hz, 2H),7.22-7.24 (m, 3H), 6.97-7.0 (m, 3H), 4.69-4.79 (m, 2H), 4.50 (t, J =12.0 Hz, 1H), 3.27 (m, 1H), 2.94 (t, J = 12.0 Hz, 1H), 2.28-2.36 (m, 2H)and 1.76-1.84 (m, 2H) 151

78% 427.32 (M + H)⁺, 98.52% CDCl₃: δ 8.62 (d, J = 6.0 Hz. 2H), 7.18-7.21 (m, 2H), 7.28 (d, J = 6.0 Hz, 2H), 7.13 (m, 2H), 7.02 (s, 1H),6.96-6.98 (m, 1H), 4.09 (t, J = 6.0 Hz, 2H), 4.0 (m, 4H), 3.89 (t, J =6.80 Hz, 2H) and 1.81 (m, 4H) 152

56% 515.16 (M + H)⁺, 94.94% δ 8.83 (br s, 1H), 8.58 (d, J = 5.60 Hz,2H), 7.77-7.83 (m, 1H), 7.46-7.53 (m, 1H), 7.18-7.33 (m, 6H, 6.73-6.76(m, 3H), 4.61 (s, 2H), 4.49 (m, 2H), 3.85 (m, 1H), 3.52 (m, 1H), 2.59(m, 2H) and 1.69-1.79 (m, 2H) 153

59% 501.12 (M + H)⁺, 98.92% δ 10.86 (br s, 1H), 8.58 (d, J = 5.60 Hz,2H), 7.80-86 (m, 1H), 7.52 (t, J = 8.40 Hz, 1H), 7.23-7.34 (m, 5H), 6.96(m, 3H), 4.73 (m, 2H), 4.49 (m, 1H), 3.36 (m, 1H), 2.94 (m, 1H),2.28-2.37 (m, 2H) and 1.75-1.84 (m, 2H) 154

46% 427.07 (M + H)⁺, 97.93% δ 8.57 (d, J = 6.0 Hz, 2H), 7.86-7.84 (m,1H), 7.52 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.40 Hz, 1H), 7.23-7.26 (m,3H), 3.88-3.91 (m, 6H), 3.71 (m, 2H) and 1.67 (m, 4H) 155

47% 523.29 (M + H)⁺, 94.27% δ 8.83 (br s, 1H), 8.57 (d, J = 5.60 Hz,2H), 7.27 (d, J = 5.60 Hz, 2H), 7.18-7.23 (m, 3H), 7.05 (d, J = 2.0 Hz,1H), 6.95 (d, J = 8.0 Hz, 1H), 6.73-6.77 (m, 4H), 6.11 (s, 2H),4.58-4.61 (m, 3H), 4.49 (m, 1H), 3.84 (m, 1H), 3.52 (m, 1H), 2.50 (m.2H) and 1.70-1.78 (m, 2H) 156

39% 507.02 (M − H)⁺, 99.10% δ 10.86 (br s, 1H), 8.58 (d, J = 6.0 Hz,2H), 7.28 (d, J = 6.0 Hz, 2H), 7.22 (m, 1H), 7.18 (s, 1H), 7.08 (d, J =1.60 Hz, 1H), 6.95-7.0 (m, 4H), 6.80 (dd, J = 2.0 and 8.40 Hzrespectively, 1H), 6.12 (s, 2H), 4.85 (d, J = 13.20 Hz, 1H), 4.72 (d, J= 11.20 Hz, 1H), 4.49 (t, J = 12.80 Hz, 1H), 3.26 (m, 1H), 2.93 (m, 1H),2.27- 2.36 (m, 2H) and 1.76-1.83 (m, 2H) 157

38% 435.06 (M + H)⁺, 98.73% δ 8.57 (d, J = 6.0 Hz, 2H), 7.26 (d, J =6.40 Hz, 2H), 7.13 (s, 1H), 7.06 (d, J = 2.0 Hz, 1H), 6.98 (d, J = 8.40Hz, 1H), 6.79 (dd, J = 2.0 and 8.0 Hz respectively, 1H), 6.13 (s, 2H),3.92-3.96 (m, 6H), 3.70 (m, 2H) and 1.67 (m, 4H) 158

43% 615.16 (M + H)⁺, 96.93% δ 8.84 (br s, 1H), 8.61 (d, J = 6.0 Hz, 2H),8.20 (s, 1H), 8.04 (m, 2H), 7.34 (d, J = 5.60 Hz, 2H), 7.20-7.25 (m,3H), 6.73- 6.79 (m, 3H), 4.62 (s, 2H), 4.40-4.50 (m, 2H), 3.86 (m, 1H),3.54 (m, 1H), 2.56 (m, 2H) and 1.70-1.80 (m, 2H) 159

70% 601.12 (M + H)⁺, 99.75% δ 10.86 (br s, 1H), 8.61 (d, J = 6.0 Hz,2H), 8.23 (s, 1H), 8.07 (m, 2H), 7.35 (d, J = 6.0 Hz, 2H), 7.24 (m, 2H),6.97-6.99 (m, 3H), 4.64-4.73 (m, 2H), 4.51 (t, J = 12.40 Hz, 1H), 3.36(m, 1H), 2.97 (t, J = 12.0 Hz, 1H), 2.33 (t, J = 13.60 Hz, 2H) and1.76-1.85 (m, 2H) 160

61% 527.07 (M + H)⁺, 95.45% δ 8.61 (d, J = 6.0 Hz, 2H), 8.23 (s, 1H),8.06 (s, 2H), 7.33 (d, J = 6.0 Hz, 2H), 7.20 (s, 1H), 3.88-3.92 (m, 6H),3.72 (m, 2H) and 1.68 (m, 4H) 161

37% 565.17 (M + H)⁺, 96.70% δ 8.84 (br s, 1H), 8.63 (d, J = 6.0 Hz, 2H),7.86 (t, J = 8.0 Hz, 1H), 7.69 (d, J = 11.60 Hz, 1H), 7.30-7.36 (m, 3H),7.20-7.24 (m, 3H), 6.73-6.78 (m, 3H), 4.62 (s, 2H), 4.48-4.50 (m, 2H),3.87 (t, J = 11.20 Hz, 1H), 3.54 (t, J = 11.60 Hz, 1H), 2.56 (m, 2H) and1.71-1.86 (m, 2H) 162

51% 551.12 (M + H)⁺. 98.94% δ 10.86 (br s, 1H), 8.63 (d, J = 5.60 Hz,2H), 7.89 (t, J = 8.0 Hz, 1H), 7.72 (d, J = 11.20 Hz, 1H), 7.35 (m, 3H),7.24 (m, 2H), 6.97-6.99 (m, 3H), 4.72 (m, 2H), 4.51 (t, J = 12.40 Hz,1H), 3.35 (m, 1H), 2.96 (t, J = 13.20 Hz, 1H), 2.29-2.40 (m, 2H) and1.76-1.85 (m, 2H) 163

56% 477.11 (M + H)⁺, 96.46% δ 8.62 (d, J = 4.80 Hz, 2H), 7.88 (t, J =8.0 Hz, 1H), 7.71 (d, J = 11.20 Hz, 1H), 7.33 (m, 3H), 7.19 (s, 1H),3.92 (m, 6H), 3.71 (m, 2H) and 1.69 (m, 4H) 164

40% 548.20 (M + H)⁺, 96.66% δ 8.84 (m, 2H), 8.64 (d, J = 6.0 Hz, 2H),8.03 (s, 2H), 7.38 (d, J = 6.0 Hz, 2H), 7.28 (s, 1H), 7.21 (t, J = 8.0Hz, 2H), 6.73-6.78 (m, 3H), 4.62 (s, 2H), 4.49-4.51 (m, 2H), 3.88 (t, J= 11.60 Hz, 1H), 3.54 (t, J = 11.60 Hz, 1H), 2.56 (m, 2H) and 1.72- 1.80(m, 2H) 165

44% 534.13 (M + H)⁺, 99.22% δ 10.86 (br s, 1H), 8.40 (s, 1H), 8.64 (d, J= 6.0 Hz, 2H), 8.03-8.09 (m, 2H), 7.38 (d, J = 6.0 Hz, 2H), 7.28 (s,1H), 7.24 (m, 1H), 6.97 (m, 3H), 4.72 (m, 2H), 4.51 (t, J = 12.0 Hz,1H), 3.35 (m, 1H), 2.97 (t, J = 12.0 Hz, 1H), 2.29-2.38 (m, 2H) and1.77-1.86 (m, 2H) 166

41% 460.15 (M + H)⁺, 98.30% δ 8.82 (br s, 1H), 8.63 (d, J = 5.20 Hz,2H), 8.05 (s, 2H), 7.36 (d, J = 6.0 Hz, 2H), 7.22 (s, 1H), 3.92 (m, 6H),3.72 (m, 2H) and 1.69 (m, 4H) 167

28% 481.28 (M + H)⁺, 97.91% δ 9.12 (s, 1H), 8.85(s, 1H), 8.69 (d, J =2.40 Hz, 1H), 8.59 (d, J = 5.60 Hz, 2H), 8.39 (s, 1H), 7.38 (d, J = 6.0Hz, 2H), 7.20-7.24 (m, 3H), 6.73-6.80 (m, 3H), 4.63 (s, 2H), 4.45-4.51(m, 2H), 3.89 (t, J = 12.40 Hz, 1H), 3.54 (t, J = 12.0 Hz, 1H), 2.62 (m,1H), 2.44 (m, 1H) and 1.74- 1.81 (m, 2H) 168

43% 467.24 (M + H)⁺, 99.30% δ 10.87 (br s, 1H), 9.17 (s, 1H), 8.72 (s,1H), 8.59 (d, J = 5.20 Hz, 2H), 8.41 (s, 1H), 7.38 (d, J = 5.20 Hz, 2H),7.24-7.26 (m, 2H), 6.97 (m, 3H), 4.73 (d, J = 13.20 Hz, 2H), 4.55 (m,1H), 3.39 (m, 1H), 2.97 (m, 1H), 2.37 (m, 2H) and 1.78-1.85 (m, 2H) 169

37% 393.34 (M + H)⁺, 99.28% δ 9.15 (s, 1H), 8.72 (m, 1H), 8.58 (d, J =6.0 Hz, 2H), 8.41 (s, 1H), 7.36 (d, J = 6.0 Hz, 2H), 7.18 (s, 1H), 3.93(m, 6H), 3.73 (m, 2H) and 1.71 (m, 4H) 170

48% 437.24 (M + H)⁺, 96.34% δ 8.56 (m, 2H), 7.47 (m, 3H), 7.38 (m, 2H),7.19-7.28 (m, 7H), 5.03 (s, 2H), 4.56-4.67 (m, 2H), 3.49 (t, J = 12.0Hz, 1H), 3.12 (t, J = 12.0 Hz, 1H), 1.89-1.96 (m, 2H) and 1.67-1.76 (m,2H) 171

51% 451.15 (M + H)⁺, 95.28% δ 8.57 (d, J = 6.0 Hz, 2H), 7.76-7.86 (m,3H), 7.61 (t, J = 8.40 Hz, 1H), 7.48-7.50 (m, 3H), 7.37-7.39 (m, 2H),7.22-7.25 (m, 3H), 4.85 (d, J = 10.40 Hz, 1H), 4.70 (m, 1H), 3.53 (m,1H), 3.16 (t, J = 10.80 Hz, 1H), 2.25-2.32 (m, 2H) and 1.71-1.79 (m, 2H)172

52% 479.12 (M + H)⁺, 98.91% δ 8.56 (d, J = 6.0 Hz, 2H), 7.47-7.50 (m,3H), 7.37-7.39 (m, 2H), 7.28-7.31 (m, 1H), 7.21-7.25 (m, 3H), 7.13-7.15(m, 1H), 7.02-7.07 (m, 2H), 4.84 (d, J = 13.20 Hz, 1H), 4.73 (d, J =12.40 Hz, 1H), 4.53 (m, 1H), 3.70 (s, 3H), 3.36 (m, 1H), 2.95 (m, 1H),2.26-2.40 (m, 2H) and 1.77-1.85 (m, 2H) 173

68% 494.39 (M + H)⁺, 97.19% δ 8.54 (d, J = 4.80 Hz, 2H), 7.48 (m, 3H),7.31-7.39 (m, 7H), 7.21 (m, 2H), 7.04- 7.11 (m, 1H), 5.01 (t, J = 8.0Hz, 1H), 4.41-4.71 (m, 3H), 3.98 (m, 1H), 3.59 (m, 1H), 3.03 (m, 1H),2.68 (m, 1H), 1.90 (m, 1H), 1.56-1.76 (m, 2H) and 1.23-1.27 (m, 1H) 174

59% 431.10 (M + H)⁺, 99.54% δ 8.91 (br s, 1H), 8.56 (d, J = 5.60 Hz,2H), 7.48-7.49 (m, 3H), 7.36-7.38 (m, 2H), 7.19-7.24 (m, 3H), 4.47 (d, J= 13.60 Hz, 1H), 4.33 (d, J = 12.80 Hz, 1H), 3.63 (t, J = 12.0 Hz, 1H),3.25 (m, 1H), 2.84 (s, 3H), 1.81-1.98 (m, 2H) and 1.66 (m, 2H)Experimental Procedures:

For the numbered schemes (e.g., Scheme 1), yields reported herein referto purified products (unless specified) and are not optimised.Analytical TLC was performed on Merck silica gel 60 F₂₅₄aluminium-backed plates. Compounds were visualised by UV light and/orstained with either 1₂ or potassium permanganate solution followed byheating. Flash column chromatography was performed on silica gel. ¹H-NMRspectra were recorded on a Bruker Avance-400 MHz spectrometer with a BBO(Broad Band Observe) and BBFO (Broad Band Fluorine Observe) probe.Chemical shifts (3) are expressed in parts per million (ppm) downfieldby reference to tetramethylsilane as the internal standard. Splittingpatterns are designated as s (singlet), d (doublet), t (triplet), q(quartet), m (multiplet) and br s (broad singlet). Coupling constants(J) are given in hertz (Hz). LCMS analyses were performed either on anAcquity BEH C-18 column (2.10×100 mm, 1.70 μm) or Acquity HSS-T3(2.1×100 mm, 1.8 μm) using the Electrospray Ionisation (ESI) technique.

The final compounds were purified via reverse-phase prep-HPLC employingeither of the 2 methods mentioned below.

-   -   1. Column: SUNFIRE C 18 (19×250) mm, 5μ particle size, Mobile        phase: A 0.1% TFA in Water, B ACN

Flow mode: Time % A % B 1.00 50 50 15.00 36 74 15.10 10 90 17.00 10 9017.10 50 50 20.00 50 50

-   -   Or    -   2. Column: X TERRA C 18 (19×250) mm, 5μ particle size, Mobile        phase: A 5 mM Ammonium Acetate n water, B ACN

Flow mode: Time % A % B 1.00 60 40 10.00 35 65 11.00 35 65 11.10 60 4014.00 60 40

Reference: WO 2005/040166 and Tett. Lett; 2007, 55, 501-502General Procedure for the Preparation of 1.5 (a-h):

General Method A:

To an ice-cold solution of 1-benzylpiperidin-4-one 1.1 (5.0-7.0 g, 1.0eq) in acetic acid was added respective amines (1.1 eq) andtrimethylsilyl cyanide (1.5 eq). The resulting reaction mass was stirredat RT for 18 h. After completion of the reaction (TLC monitoring), thereaction mass was cooled to 0° C. and the pH adjusted to ˜10 using 5.0 Nsodium hydroxide solution. The aqueous part was extracted with DCM(3×250 mL). The combined organics were dried over anhydrous Na₂SO₄,filtered and concentrated. The crude was triturated with diethyl etherto get the desired product 1.2 (a-h) as off white solid.

1-Benzyl-4-((4-fluorophenyl)amino)piperidine-4-carbonitrile (1.2-a)

¹H-NMR (400 MHz, CDCl₃): δ 7.35-7.38 (m, 5H), 6.90-6.95 (m, 4H), 3.54(s, 2H), 3.48 (br s, 1H), 2.80-2.84 (m, 2H), 2.38-2.41 (m, 2H),2.22-2.24 (m, 2H) and 1.89-1.94 (m, 2H). LC-MS: 310.23 (M+H)+, 95.66%.Yield: 58%.

1-Benzyl-4-((3,4-difluorophenyl)amino)piperidine-4-carbonitrile (1.2-b)

¹H-NMR (400 MHz, CDCl₃): δ 7.27-7.31 (m, 5H), 7.03-7.08 (m, 1H),6.75-6.79 (m, 1H), 6.60-6.63 (m, 1H), 3.59 (br s, 1H), 3.55 (s, 2H),2.80-2.84 (m, 2H), 2.41-2.47 (m, 2H), 2.26-2.39 (m, 2H) and 1.87-1.89(m, 2H). LC-MS: 328.42 (M+H)⁺, 94.27%. Yield: 40%.

1-Benzyl-4-((3-chloro-4-fluorophenyl)amino)piperidine-4-carbonitrile(1.2-c)

¹H-NMR (400 MHz, CDCl₃): δ 7.28-7.34 (m, 5H), 7.01-7.05 (m, 1H),6.95-6.97 (m, 1H), 6.79-6.82 (m, 1H), 3.57 (s, 3H), 2.80-2.83 (m, 2H),2.41-2.46 (m, 2H), 2.24-2.27 (m, 2H) and 1.87-1.92 (m, 2H). LC-MS:344.28 (M+H)⁺, 99.52%. Yield: 32%.

1-Benzyl-4-((3,4,5-trifluorophenyl)amino)piperidine-4-carbonitrile(1.2-d)

¹H-NMR (400 MHz, CDCl₃): δ 7.31-7.34 (m, 5H), 6.48-6.51 (m, 2H), 3.73(s, 1H), 3.56 (s, 2H), 2.75-2.80 (m, 2H), 2.45-2.48 (m, 2H), 2.29-2.32(m, 2H) and 1.86-1.88 (m, 2H). MS: 346.00 (M+H)⁺, 99.52%. Yield: 25%.

1-Benzyl-4-((4-fluoro-3-(trifluoromethyl)phenyl)amino)piperidine-4-carbonitrile(1.2-e)

¹H-NMR (400 MHz, CDCl₃): δ 7.29-7.31 (m, 5H), 7.10-7.11 (m, 3H), 3.69(s, 1H), 3.56 (s, 2H), 2.82-2.85 (m, 2H), 2.45-2.48 (m, 2H), 2.19-2.22(m, 2H) and 1.92-1.92 (m, 2H). LC-MS: 378.33 (M+H)⁺, 94.03%. Yield: 45%.

1-Benzyl-4-((4-fluoro-3,5-dimethylphenyl)amino)piperidine-4-carbonitrile(1.2-f)

¹H-NMR (400 MHz, CDCl₃): δ 7.26-7.31 (m, 5H), 6.55-6.57 (m, 1H),6.37-6.38 (m, 1H), 3.60 (s, 1H), 3.53 (s, 2H), 2.76-2.81 (m, 2H),2.45-2.50 (m, 2H), 2.28-2.32 (m, 2H), 2.09 (m, 6H), and 1.88-1.93 (m,2H). MS: 338.33 (M+H)⁺, Yield: 60%.

1-Benzyl-4-((4-fluoro-2-methoxyphenyl)amino)piperidine-4-carbonitrile(1.2-g)

¹H-NMR (400 MHz, CDCl₃): δ 7.31-7.35 (m, 5H), 6.99-7.03 (m, 1H),6.58-6.62 (m, 2H), 4.09 (s, 1H), 3.82 (s, 3H), 3.55 (s, 2H), 2.73-2.76(m, 2H), 2.44-2.47 (m, 2H), 2.27-2.31 (m, 2H) and 1.90-1.93 (m, 2H). MS:340.25 (M+H)⁺. Yield: 60%.

1-Benzyl-4-((4-(difluoromethoxy)phenyl)amino)piperidine-4-carbonitrile(1.2-h)

¹H-NMR (400 MHz, CDCl₃): δ 7.25-7.34 (m, 5H), 7.02 (d, J=8.8 Hz, 2H),6.89 (d, J=8.8 Hz, 2H), 3.61 (br s, 1H), 3.49 (s, 3H), 2.80-2.83 (m,2H), 2.43-2.47 (m, 2H), 2.17-2.22 (m, 2H) and 1.88-1.94 (m, 2H). LC-MS:358.0 (M+H)⁺, 96.98%. Yield: 52.23%.

General Procedure for the Preparation of 1.3 (a-h): General Method B:

An ice-cold solution of 1.2 (a-g) (3.0-4.0 g, 1.0 eq) in 90% aqueoussulphuric acid was stirred at 0° C. for 30.0 min, then warm up to RT andstirred for 16 h. After completion of the reaction (TLC monitoring), thereaction mass was cooled to 0° C. and the pH adjusted to ˜10 using 5.0 Nsodium hydroxide solution. The aqueous part was extracted with DCM. Thecombined organics were dried over anhydrous sodium sulphate, filteredand concentrated. The crude was triturated with diethyl ether to get thedesired products 1.3 (a-g) as off-white solids.

General Method C:

To an ice-cold solution of1-benzyl-4-((4-(difluoromethoxy)phenyl)amino)piperidine-4-carbonitrile1.2-h (2.5 g, 7.0 mmol, 1.0 eq) in DMSO was added H₂O₂ (30% aqueoussolution, 1.5 eq) and K₂CO₃ (0.2 eq). The resulting reaction mixture wasstirred at RT for 30.0 min. After completion of reaction (TLCmentoring), H₂O was added and extracted with DCM (3 times). The combinedorganics were dried over anhydrous sodium sulphate, filtered andconcentrated. The crude was triturated with diethyl ether to get thedesired product 1.3-h as an off-white solid.

1-Benzyl-4-(4-fluorophenylamino)piperidine-4-carboxamide (1.3-a)

¹H-NMR (400 MHz, CDCl₃): δ 7.23-7.25 (m, 5H), 6.85-6.87 (m, 3H),6.54-6.55 (m, 2H), 5.47 (br s, 1H), 3.93 (s, 1H), 3.48 (s, 2H),2.72-2.74 (m, 2H), 2.28-2.29 (m, 2H), 2.04-2.07 (m, 2H) and 1.86-1.89(m, 2H). LCMS: 328.22 (M+H)⁺, 98.42%. Yield: 84%.

1-Benzyl-4-((3,4-difluorophenyl)amino)piperidine-4-carboxamide (1.3-b)

¹H-NMR (400 MHz, CDCl₃): δ 7.31-7.33 (m, 5H), 6.89-6.92 (m, 1H), 6.79(br s, 1H), 6.45-6.48 (m, 1H), 6.29-6.31 (m, 1H), 5.51 (br s, 1H), 3.98(s, 1H), 3.49 (s, 2H), 2.74-2.75 (m, 2H), 2.28-2.31 (m, 2H), 2.04-2.07(m, 2H) and 1.85-1.87 (m, 2H). LCMS: 346.14 (M+H)⁺, 94.52%. Yield: 85%.

1-Benzyl-4-((3-chloro-4-fluorophenyl)amino)piperidine-4-carboxamide(1.3-c)

¹H-NMR (400 MHz, CDCl₃): δ 7.28-7.32 (m, 6H), 7.07-7.00 (m, 2H), 6.68(br s, 1H), 6.50 (br s, 1H), 5.75 (br s, 1H), 3.42 (s, 2H), 2.50-2.52(m, 2H), 2.22-2.24 (m, 2H), 1.98-2.00 (m, 2H) and 1.76-1.79 (m, 2H).LCMS: 362.05 (M+H)⁺, 90.00%. Yield: 79%.

1-Benzyl-4-((3,4,5-trifluorophenyl)amino)piperidine-4-carboxamide(1.3-d)

¹H-NMR (400 MHz, CDCl₃): δ 7.28-7.34 (m, 6H), 7.11 (br s, 1H), 6.31-6.35(m, 2H), 6.11 (br s, 1H), 3.48 (s, 2H), 2.50-2.53 (m, 2H), 2.22-2.25 (m,2H), 1.95-1.97 (m, 2H) and 1.77-1.80 (m, 2H). LCMS: 364.00 (M+H)⁺,91.64%. Yield: 40%.

1-Benzyl-4-((4-fluoro-3-(trifluoromethyl)phenyl)amino)piperidine-4-carboxamide(1.3-e)

¹H-NMR (400 MHz, CDCl₃): δ 7.28-7.35 (m, 5H), 7.17-7.22 (m, 2H), 7.08(br s, 1H), 6.94-6.95 (m, 1H), 6.73-6.75 (m, 1H), 6.00 (br s, 1H), 3.42(s, 2H), 2.49-2.53 (m, 2H), 2.23-2.28 (m, 2H), 1.97-2.02 (m, 2H) and1.76-1.80 (m, 2H). LCMS: 396.20 (M+H)⁺, 95.56%. Yield: 45%.

1-Benzyl-4-((4-fluoro-3,5-dimethylphenyl)amino)piperidine-4-carboxamide(1.3-f)

¹H-NMR (400 MHz, CDCl₃): δ 7.28-7.34 (m, 6H), 7.15 (br s, 1H), 7.01 (s,1H), 6.21-6.27 (m, 2H), 3.48 (s, 2H), 2.50-2.51 (m, 2H), 2.22-2.24 (m,2H), 2.06 (d, J=6.0 Hz, 6H), 1.96-1.99 (m, 2H) and 1.77-1.81 (m, 2H).MS: 356.37 (M+H)⁺. Yield: 56.6%.

1-Benzyl-4-((4-fluoro-2-methoxyphenyl)amino)piperidine-4-carboxamide(1.3-g)

¹H-NMR (400 MHz, CDCl₃): δ 7.22-7.30 (m, 6H), 7.05 (br s, 1H), 6.80-6.83(m, 1H), 6.54-6.58 (m, 1H), 6.25-6.28 (m, 1H), 4.55 (s, 1H), 3.82 (s,3H), 3.33-3.38 (m, 2H), 2.54-2.56 (m, 2H), 1.94-2.08 (m, 4H) and1.80-1.83 (m, 2H). LCMS: 358.40 (M+H)⁺, 99.78%. Yield: 61.38%.

1-Benzyl-4-((4-(difluoromethoxy)phenyl)amino)piperidine-4-carboxamide(1.3-h)

¹H-NMR (400 MHz, CDCl₃): δ 7.21-7.29 (m, 6H), 7.02 (br s, 1H), 6.90-6.95(m, 3H), 6.56 (d, J=8.8 Hz, 2H), 3.42 (s, 3H), 2.53-2.59 (m, 2H),2.32-2.36 (m, 2H), 1.99-2.11 (m, 2H) and 1.82-1.90 (m, 2H). MS: 376.30(M+H)⁺. Yield: 30%.

General Procedure for the Preparation of 1.4 (a-h):

General Method D:

A solution of compounds 1.3 (a-c) (2.0-4.0 g, 1.0 eq), intriethylorthoformate and AcOH (3:1) was irradiated by microwave in asealed tube to 190° C. for 2 h. The reaction mixture was diluted withwater and extracted with EtOAc. The combined organics were washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated. Theresidue was purified over silica gel (100-200 M, 2-4% MeOH-DCM) to getthe desired products 1.4 (a-c) as off-white solids.

General Method E:

To a solution of compounds 1.3 (a-h) (1.0-2.5 g, 1.0 eq) in methanol wasadded DMF-DMA (3.0 eq). The resulting reaction mass was heated at 65° C.for h. After completion of reaction (TLC monitoring), the solvent wasevaporated to dryness. The resulting crude residue was triturated withdiethyl ether to get the desired product as an off-white solid product1.4 (a-h).

8-Benzyl-1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one (1.4-a)

H-NMR (400 MHz, DMSO-d₆): δ 8.65 (s, 1H), 7.44-7.46 (m, 2H), 7.31-7.34(m, 2H), 7.13-7.16 (m, 5H), 3.41 (s, 2H), 2.66-2.69 (m, 2H), 2.41-2.44(m, 2H) and 1.75-1.78 (m, 4H). MS: 338.22 (M+H)⁺. Yield: 48% with methodD and 89% with method E.

8-Benzyl-1-(3,4-difluorophenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one(4-b)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.69 (s, 1H), 7.66-7.71 (m, 1H), 7.56-7.61(m, 1H), 7.19-7.30 (m, 6H), 3.47 (s, 2H), 2.72-2.78 (m, 2H), 2.43-2.46(m, 2H) and 1.72-1.80 (m, 4H). LCMS: 356.40 (M+H)⁺, 87.67%. Yield: 22%with method D and 85% with method E.

8-Benzyl-1-(3-chloro-4-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one(1.4-c)

LCMS: 372.40 (M+H)+, 75.07%. Yield: 20% with method D.

8-Benzyl-1-(3,4,5-trifluorophenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one(1.4-d)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.71 (s, 1H), 7.57-7.60 (m, 2H), 7.24-7.28(m, 5H), 3.49 (s, 2H), 2.73-2.75 (m, 2H), 2.48-2.49 (m, 2H), 1.83-1.85(m, 2H) and 1.71-1.77 (m, 2H). MS: 373.96 (M+H)⁺. Yield: 65% with methodE.

8-benzyl-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one(1.4-e)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.22 (s, 1H), 7.33-7.42 (m, 8H), 3.50 (s,2H), 2.92-2.95 (m, 2H), 2.68-2.70 (m, 2H), 1.90-1.91 (m, 2H) and1.72-1.73 (m, 2H). MS: 406.56 (M+H)⁺. Yield: 63% with method E.

8-Benzyl-1-(4-fluoro-3,5-dimethylphenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one(1.4-f)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.15 (s, 1H), 7.48-7.49 (m, 4H), 7.26-7.28(m, 1H), 7.80-7.81 (m, 2H), 3.60 (s, 2H), 2.87-2.91 (m, 2H), 2.59-2.61(m, 2H), 2.28 (s, 6H), 1.88-1.89 (m, 2H) and 1.56-1.58 (m, 2H). MS:366.35 (M+H)⁺. Yield: 79% with method E.

8-Benzyl-1-(4-fluoro-2-methoxyphenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one(1.4-g)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.01 (s, 1H), 7.22-7.26 (m, 5H), 7.08-7.12(m, 1H), 6.70-6.74 (m, 2H), 3.77 (s, 3H), 3.55 (s, 2H), 2.87-2.95 (m,2H), 2.59-2.62 (m, 2H) and 1.83-1.98 (m, 4H). LCMS: 368.00 (M+H)⁺,90.91%. Yield: 78% with method E.

8-Benzyl-1-(4-(difluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one(1.4-h)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.67 (s, 1H), 7.45 (d, J=8.8 Hz, 2H), 7.30(d, J=8.8 Hz, 2H), 7.21-7.26 (m, 5H), 3.46 (s, 2H), 3.28-3.32 (m, 1H),2.67-2.72 (m, 2H), 2.45-2.49 (m, 2H) and 1.74-1.75 (m, 4H). MS: 386.0(M+H)⁺. Yield: 53% with method E.

General Procedure for the Preparation of 1.5 (a-h):

General Method F:

To a solution of compounds 1.4 (a-h) (0.50-1.5 g, 1.0 eq) in MeOH andAcOH (40:1, 20 mL) were added Pd—C (10 mol % w/w) and the resultingsolution was stirred under hydrogen atmosphere (1 atm) at ambienttemperature for 16 h. The reaction mixture was filtered throughdiatomaceous earth (Celite) bed and the filtrate was concentrated underreduced pressure. The residue was purified over silica gel (basicalumina, 2-4% MeOH-DCM) to get the desired products 1.5 (a-h) as offwhite solids.

1-(4-Fluorophenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one (1.5-a):Intermediate 1

¹H-NMR (400 MHz, DMSO-d₆): δ 8.81 (br s, 1H), 7.05-7.08 (m, 2H),6.95-6.96 (m, 2H), 4.58 (s, 2H), 3.34-3.37 (m, 3H), 2.97-2.99 (m, 2H),2.35-2.36 (m, 2H) and 1.61-1.63 (m, 2H). LCMS: 250.23 (M+H)⁺, 88.25%.Yield: 90%

1-(3,4-Difluorophenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one (1.5-b):Intermediate 2

¹H-NMR (400 MHz, DMSO-d₆): δ 8.77 (br s, 1H), 7.17-7.28 (m, 2H),6.90-6.94 (m, 1H), 6.68-6.71 (m, 1H), 4.55 (s, 2H), 3.22-3.25 (m, 2H),2.94-2.97 (m, 2H), 2.37-2.40 (m, 2H) and 1.54-1.57 (m, 2H). MS: 268.25(M+H)⁺. Yield: 86%

1-(3-Chloro-4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (1.5-c):Intermediate 3

MS: 284.12 (M+H)⁺. Yield: 50%.

1-(3,4,5-Trifluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (1.5-d):Intermediate 4

¹H-NMR (400 MHz, DMSO-d₆): δ 9.27 (s, 1H), 9.07 (s, 1H), 6.90-6.92 (m,1H), 4.59 (s, 2H), 3.28-3.33 (m, 2H), 2.74-2.76 (m, 2H), 2.50-2.52 (m,2H) and 1.82-1.85 (m, 2H). MS: 286.24 (M+H)⁺. Yield: 60%.

1-(4-Fluoro-3-(trifluoromethyl)phenyl)-1,3,8-triazaspiro[4.5]decan-4-one(1.5-e): Intermediate 5

¹H-NMR (400 MHz, DMSO-d₆): δ 8.77 (br s, 1H), 7.33-7.35 (m, 2H),6.92-6.93 (m, 1H), 6.70-6.71 (m, 1H), 4.62 (s, 2H), 3.17-3.20 (m, 2H),2.88-2.90 (m, 2H), 2.33-2.39 (m, 2H) and 1.53-1.56 (m, 2H). LCMS: 318.29(M+H)⁺, 90.82%. Yield: 64%.

1-(4-Fluoro-3,5-dimethylphenyl)-1,3,8-triazaspiro[4.5]decan-4-one(1.5-f): Intermediate-6

¹H-NMR (400 MHz, DMSO-d₆): δ 8.83 (s, 1H), 7.66-7.68 (m, 1H), 6.60-6.66(m, 2H), 4.54 (s, 2H), 3.38-3.41 (m, 2H), 3.12-3.16 (m, 2H), 2.50-2.53(m, 2H), 2.19 (s, 6H) and 1.67-1.70 (m, 2H). MS: 278.32 (M+H)⁺. Yield:80%.

1-(4-Fluoro-2-methoxyphenyl)-1,3,8-triazaspiro[4.5]decan-4-one (1.5-g):Intermediate 7

¹H-NMR (400 MHz, DMSO-d₆): δ 8.51 (s, 1H), 7.62-7.69 (m, 1H), 7.22-7.26(m, 1H), 6.92-6.98 (m, 1H), 6.72-6.76 (m, 1H), 4.66 (s, 2H), 3.76 (s,3H), 3.19-3.26 (m, 2H), 2.90-3.01 (m, 2H), 2.50-2.54 (m, 2H) and1.50-1.52 (m, 2H). MS: 280.26 (M+H)⁺. Yield: 71%.

1-(4-(Difluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]decan-4-one (1.5-h):Intermediate 8

¹H-NMR (400 MHz, DMSO-d₆): δ 9.05 (br s, 1H), 7.10-7.13 (m, 3H),6.93-6.96 (m, 2H), 4.57 (s, 2H), 3.25-3.28 (m, 3H), 2.97-2.99 (m, 2H),2.40-2.42 (m, 2H) and 1.59-1.64 (m, 2H). MS: 298.34 (M+H)⁺. Yield: 78%.

General Procedure for the Preparation of 2.6 (a-b):

Prepared following general method A.

1-Benzyl-4-((4-bromophenyl)amino)piperidine-4-carbonitrile (2.6-a)

¹H-NMR (400 MHz, CDCl₃): δ 7.35-7.38 (m, 7H), 6.79 (d, J=8.4 Hz, 2H),6.30 (br s, 1H), 3.51 (s, 2H), 2.74-2.76 (m, 2H), 2.28-2.31 (m, 4H) and1.81-1.83 (m, 2H). MS: 369.98 (M+H)⁺. Yield: 52%.

1-Benzyl-4-((4-iodophenyl)amino)piperidine-4-carbonitrile (2.6-b)

¹H-NMR (400 MHz, CDCl₃): δ 7.45 (d, J=7.6 Hz, 2H), 7.26-7.30 (m, 5H),6.68 (d, J=2.0 Hz, 2H), 6.32 (br s, 1H), 3.51 (s, 2H), 2.73-2.75 (m,2H), 2.28-2.34 (m, 4H) and 1.81-1.83 (m, 2H). MS: 418.35 (M+H)⁺. Yield:40%.

General Procedure for the Preparation of 2.7 (a-b):

Prepared following general method B.

1-Benzyl-4-(4-bromophenylamino)piperidine-4-carboxamide (2.7-a)

¹H-NMR (400 MHz, CDCl₃): δ 7.34-7.56 (m, 10H), 6.51-6.53 (m, 2H), 3.41(s, 2H), 2.66-2.72 (m, 2H), 2.23-2.26 (m, 2H), 1.96-1.98 (m, 2H) and1.78-1.82 (m, 2H). MS: 388.26 (M+H)⁺. Yield: 60%.

1-Benzyl-4-(iodophenylamino)piperidine-4-carboxamide (2.7-b)

¹H-NMR (400 MHz, CDCl₃): δ 7.26-7.37 (m, 8H), 7.01 (s, 1H), 6.41 (d,J=8.4 Hz, 2H), 5.72 (br s, 1H), 3.41 (s, 2H), 2.49-2.52 (m, 2H),2.20-2.25 (m, 2H), 1.95-2.00 (m, 2H) and 1.78-1.81 (m, 2H). LCMS: 436.32(M+H)⁺, 93.67%. Yield: 41%.

General Procedure for the Preparation of 2.8 (a-b):

Prepared following general method E.

8-Benzyl-1-(4-bromophenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one (2.8-a)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.25 (s, 1H), 7.60 (d, J=8.4 Hz, 2H),7.26-7.31 (m, 5H), 7.08 (d, J=7.2 Hz, 2H), 3.59 (s, 2H), 2.86-2.88 (m,2H), 2.30-2.35 (m, 2H), 2.02-2.06 (m, 2H) and 1.65-1.68 (m, 2H). LCMS:398.31 (M+H)+, 83.8%. Yield: 89%.

8-Benzyl-1-(4-iodophenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one (2.8-b)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.70 (s, 1H), 7.86 (d, J=8.4 Hz, 2H),7.19-7.30 (m, 7H), 3.47 (s, 2H), 2.72-2.78 (m, 2H), 2.46-2.49 (m, 2H)and 1.70-1.79 (m, 4H). MS: 446.18 (M+H)⁺. Yield: 59%.

General Procedure for the Preparation of 2.9 (a-b):

General Method G:

To an ice-cold solution of compound 2.8 (a-b) (1.0-1.5 g, 1.0 eq) inmethanol was added NaBH₄ (2.5 eq) portion-wise. The resulting reactionmixture was stirred at RT for 2 h. After completion of reaction (TLCmonitoring), cooled to 0° C. added water and extracted with EtOAc (3times). The combined organics were washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated. The crude was trituratedwith diethyl ether to get desired products 2.9 (a-b) as off whitesolids.

8-Benzyl-1-(4-bromophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (2.9-a)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.66 (s, 1H), 7.39 (d, J=8.8 Hz, 2H),7.31-7.34 (m, 4H), 7.24-7.26 (m, 1H), 6.79 (d, J=8.8 Hz, 2H), 4.55 (s,2H), 3.52-3.54 (m, 2H), 2.66-2.71 (m, 4H) and 1.54-1.58 (m, 4H). LCMS:400.32 (M+H)⁺, 98.11%. Yield: 83%.

8-Benzyl-1-(4-iodophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (2.9-b)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.66 (s, 1H), 7.53 (d, J=8.8 Hz, 2H),7.31-7.34 (m, 4H), 7.24 (br s, 1H), 6.67 (d, J=8.4 Hz, 2H), 4.50 (s,2H), 3.52-3.53 (m, 2H), 2.66-2.69 (m, 4H) and 1.53-1.57 (m, 4H). LCMS:448.20 (M+H)⁺, 96.28%. Yield: 91%.

General Procedure for the Preparation of 2.10 (a-b):

General Method H:

To an ice-cold solution of 2.9 (a-b) (0.50-1.0 g, 1.0 eq) in DCE wasadded 1-chloroethyl chloroformate (2.0 eq). The resulting reactionmixture was refluxed for 5 h. After completion of reaction (TLCmonitoring), solvent was evaporated to dryness. The crude residue wasdissolved in MeOH and heated at 65° C. for 16 h. After completion ofreaction (TLC monitoring), solvent was evaporated. The crude waspurified over silica gel (100-200M), and eluted with 3-5% MeOH/DCM toget the desired products 2.10 (a-b) as off-white solids.

1-(4-Bromophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (2.10-a):Intermediate 9

LCMS: 310.16 (M+H)⁺, 87.90%. Yield: 43%.

1-(4-Iodophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (2.10-b):Intermediate 10

¹H-NMR (400 MHz, DMSO-d₆): δ 9.34 (br s, 1H), 8.99 (s, 1H), 7.45 (d,J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 4.61 (s, 2H), 3.51-3.53 (m, 2H),3.28-3.33 (m, 2H), 2.79-2.83 (m, 2H) and 1.75-1.79 (m, 2H). LCMS: 358.17(M+H)⁺, 89.37%. Yield: 68%.

Preparation of8-benzyl-3-((4-fluorophenyl)amino)-8-azabicyclo[3.2.1]octane-3-carbonitrile(3.12)

Prepared following general method A. MS: 336.14 (M+H)⁺. Yield: 32%.

Preparation of8-benzyl-3-((4-fluorophenyl)amino)-8-azabicyclo[3.2.1]octane-3-carboxamide(3.13)

Prepared following general method B. ¹H-NMR (400 MHz, DMSO-d₆): δ 7.63(br s, 1H), 7.46-7.52 (m, 2H), 7.41-7.46 (m, 2H), 7.26-7.30 (m, 3H),6.87-6.91 (m, 2H), 6.59 (br s, 2H), 5.44 (m, 1H), 4.15 (m, 1H),3.83-3.85 (s, 2H), 3.37-3.40 (m, 2H), 2.72-2.78 (m, 2H), 2.12-2.17 (m,2H) and 1.80-1.90 (m, 2H). LCMS: 354.36 (M+H)⁺, 93.06%. Yield: 45%.

Preparation of8-benzyl-3′-(4-fluorophenyl)-8-azaspiro[bicycle[3.2.1]octane-3,4′-imidazol]-5′(3′H)-one(3.14)

The compound was prepared following general method E. MS: 363.98 (M+H)⁺.Yield: 50%.

Preparation of3′-(4-fluorophenyl)-8-azaspiro[bicyclo[3.2.1]octane-3,4′-imidazolidin]-5′-one(3.15)

Intermediate 11: The compound was prepared following the general methodF. MS: 276.18 (M+H)⁺. Yield: 29%.

Preparation of8-benzyl-1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione(7.27)

To an ice-cold solution of1-benzyl-4-((4-fluorophenyl)amino)piperidine-4-carbonitrile 1.2-a (1.0g, 3.23 mmol) in CHCl₃ (50 mL) was added chlorosulfonyl isocyanate (0.56mL, 6.47 mmol). The reaction mass was stirred at RT for 1 h. Aftercompletion of the reaction (TLC monitoring), the reaction mass wasconcentrated to get off white solid product, which was dissolved in1M-HCl (100 mL) and heated at 100° C. for 2 h. After completion of thereaction (TLC monitoring), reaction mass was cooled to 0° C. andadjusted the pH˜10 using 5N—NaOH solution. The resulting solid wasfiltered and washed with diethyl ether to get desired product 7.27 (1.0g, 87%) as an off-white solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 11.08 (br s,1H), 7.19-7.32 (m, 9H), 3.31-3.37 (m, 2H), 2.55-2.65 (m, 4H), 1.94-1.97(m, 2H) and 1.58-1.63 (m, 2H). LCMS: 354.36 (M+H)⁺, 98.93%.

Preparation of 1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione(7.28)

Intermediate 15 was prepared following the general method F: ¹H-NMR (400MHz, DMSO-d₆): δ 8.61 (br s, 1H), 7.30-7.32 (m, 4H), 5.75-5.77 (m, 1H),2.55-2.58 (m, 4H) and 1.84-1.92 (m, 4H). MS: 264.27 (M+H)⁺. Yield: 94%.

General Procedure for the Preparation of 8.30 (a-g):

General Method I:

To an ice-cold solution of tert-butyl 4-aminopiperidine-1-carboxylate8.24 (1.0-2.5 g, 1.0 eq) in DMF was added DIPEA (1.5 eq) and respectivenitro compounds 8.29 (a-g) (1.0 eq). The resulting reaction mixture wasstirred at RT for 2-3 h. After completion of the reaction (TLCmonitoring), the reaction mass was diluted with ice-cold water andextracted with EtOAc (3 times). The combined organics were washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated. The crudewas purified over silica gel (100-200 M, 10-15% EtOAc-hexane) to get thedesired product 8.30 (a-g).

tert-Butyl 4-((2,3-difluoro-6-nitrophenyl)amino)piperidine-1-carboxylate(8.30-a)

¹H-NMR (400 MHz, CDCl₃): δ 8.00-8.04 (m, 1H), 7.94 (d, J=8.0 Hz, 1H),6.48-6.54 (m, 1H), 4.01-4.02 (m, 3H), 2.94-2.99 (m, 2H), 2.04-2.06 (m,2H) and 1.46-1.49 (m, 11H). LCMS: 356.52 (M−H)⁺, 99.10%. Yield: 56%.

tert-Butyl4-((3-fluoro-6-nitro-2-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate(8.30-b)

¹H-NMR (400 MHz, CDCl₃): δ 8.25-8.28 (m, 1H), 7.03 (m, 1H), 6.67-6.71(m, 1H), 4.01-4.04 (m, 2H), 3.39-3.42 (m, 1H), 2.78-2.84 (m, 2H),1.91-1.93 (m, 2H), 1.45 (s, 9H) and 1.40-1.41 (m, 2H). LCMS: 406.19(M−H)⁺, 88.60%. Yield: 78%.

tert-Butyl4-((3-fluoro-2-methyl-6-nitrophenyl)amino)piperidine-1-carboxylate(8.30-c)

¹H-NMR (400 MHz, CDCl₃): δ 7.98-8.02 (m, 1H), 8.62-8.67 (m, 1H),3.97-4.02 (m, 2H), 2.48 (s, 1H), 3.38-3.40 (m, 1H), 2.80-2.86 (m, 2H),2.24 (s, 3H), 1.85-188 (m, 2H), 1.44 (s, 9H) and 1.34-1.37 (m, 2H).LCMS: 352.28 (M−H)⁺, 99.33%. Yield: 40%.

tert-Butyl 4-((3-nitropyridin-2-yl)amino)piperidine-1-carboxylate(8.30-d)

¹H-NMR (400 MHz, CDCl₃): δ 8.38-8.41 (m, 2H), 8.15-8.16 (m, 1H),6.63-6.66 (m, 1H), 4.32-4.39 (m, 1H), 2.48 (s, 1H), 4.05-4.07 (m, 1H),2.96-3.02 (m, 2H), 2.04-2.07 (m, 2H), 1.55-1.62 (m, 2H) and 1.48 (s,9H). LCMS: 321.24 (M−H)⁺, 95.81%. Yield: 80%.

tert-Butyl 4-((5-cyano-2-nitrophenyl)amino)piperidine-1-carboxylate(8.30-e)

¹H-NMR (400 MHz, CDCl₃): δ 8.25 (d, J=8.8 Hz, 1H), 8.25 (m, J=7.2 Hz,1H), 7.17 (s, 1H), 6.86 (d, J=8.8 Hz, 1H), 4.04-4.10 (m, 2H), 3.60-3.67(m, 1H), 3.03-3.08 (m, 2H), 2.03-2.07 (m, 2H), 1.57-1.63 (m, 2H) and1.51 (s, 9H). LCMS: 345.22 (M−H)⁺, 99.0%. Yield: 75.3%.

tert-Butyl4-((4-cyano-5-fluoro-2-nitrophenyl)amino)piperidine-1-carboxylate(8.30-f)

¹H-NMR (400 MHz, CDCl₃): δ 8.51-8.56 (m, 2H), 6.60-6.63 (m, 1H),4.05-4.12 (m, 2H), 3.57-3.61 (m, 1H), 3.01-3.06 (m, 2H), 2.04-2.06 (m,2H), 1.54-1.63 (m, 2H) and 1.47 (s, 9H). LCMS: 363.20 (M−H)⁺, 87.37%.Yield: 82%

tert-Butyl4-((2,3,4-trifluoro-6-nitrophenyl)amino)piperidine-1-carboxylate(8.30-g)

¹H-NMR (400 MHz, CDCl₃): δ 7.77-7.93 (m, 2H), 3.94-4.04 (m, 3H),2.92-2.98 (m, 2H), 2.01-2.04 (m, 2H) and 1.25-1.30 (m, 11H). MS: 376.12(M+H)⁺. Yield: 47%

General Procedure for the Preparation of 8.31 (a-d, f, g):

General Method J:

To a solution of compound 8.30 (a-d, f, g) (1.0-2.5 g, 1.0 eq) in EtOAcwere added Pd—C (w/w, 10 mol %) and the resulting solution was stirredunder hydrogen atmosphere (1 atm) at ambient temperature for 16 h. Thereaction mixture was filtered through diatomaceous earth (Celite) bedand the filtrate was concentrated under reduced pressure to get thedesired product 8.31 (a-d, f, g).

tert-Butyl 4-((6-amino-2,3-difluorophenyl)amino)piperidine-1-carboxylate(8.31-a)

¹H-NMR (400 MHz, DMSO-d₆): δ 6.58-6.65 (m, 1H), 6.33-6.36 (m, 1H), 4.80(br s, 2H), 3.87-4.05 (m, 3H), 3.17-3.20 (m, 1H), 2.73-2.75 (m, 2H),1.73-1.76 (m, 2H), 1.39 (s, 9H) and 1.23-1.25 (m, 2H). LCMS: 328.41(M+H)⁺, 97.70%. Yield: 97%.

tert-Butyl4-((6-amino-3-fluoro-2-(trifluoromethyl)phenyl)amino)piperidine-1-carboxylate(8.31-b)

¹H-NMR (400 MHz, DMSO-d₆): δ 6.85-6.89 (m, 1H), 6.70-6.79 (m, 1H), 4.90(br s, 2H), 3.92-3.99 (m, 3H), 3.09-3.11 (m, 1H), 2.64-2.68 (m, 2H),1.69-1.73 (m, 2H), 1.38 (s, 9H) and 1.26-1.27 (m, 2H). LCMS: 356.30(M−H)⁺, 96.01%. Yield: 75%.

tert-Butyl4-((6-amino-3-fluoro-2-methylphenyl)amino)piperidine-1-carboxylate(8.31-c)

¹H-NMR (400 MHz, DMSO-d₆): δ 6.62-6.64 (m, 1H), 6.51-6.53 (m, 1H),4.10-4.12 (m, 3H), 3.41-3.45 (m, 2H), 3.11-3.14 (m, 1H), 2.66-2.69 (m,2H), 2.14 (s, 3H), 1.85-1.86 (m, 2H), 1.42 (s, 9H) and 1.27-1.29 (m,2H). LCMS: 324.31 (M−H)⁺, 88.69%. Yield: 80%.

tert-Butyl 4-((3-aminopyridin-2-yl)amino)piperidine-1-carboxylate(8.31-d)

¹H-NMR (400 MHz, CDCl₃): δ 6.68-6.69 (m, 1H), 7.86-7.88 (m, 1H),6.51-6.55 (m, 1H), 4.49-4.53 (br s, 1H), 3.98-4.12 (m, 3H), 3.45-3.48(m, 2H), 2.97-2.99 (m, 2H), 2.04-2.09 (m, 2H), 1.48 (s, 9H) and1.30-1.32 (m, 2H). LCMS: 293.23 (M+H)⁺, 98.28%. Yield: 85%.

Tert-butyl4-((2-amino-4-cyano-5-fluorophenyl)amino)piperidine-1-carboxylate(8.31-f)

¹H-NMR (400 MHz, CDCl₃): δ 6.84 (d, J=6.4 Hz, 1H), 6.31 (d, J=7.2 Hz,1H), 4.38-4.40 (m, 1H), 4.06 (br s, 2H), 3.38-3.41 (m, 1H), 2.92-3.06(m, 4H), 2.01-2.04 (m, 2H) and 1.46 (s, 11H). LCMS: 333.0 (M−H)⁺,98.21%. Yield: 76%.

Tert-butyl4-((6-amino-2,3,4-trifluorophenyl)amino)piperidine-1-carboxylate(8.31-g)

¹H-NMR (400 MHz, DMSO-d₆): δ 6.37-6.42 (m, 1H), 5.16 (br s, 2H),3.84-3.89 (m, 3H), 3.01 (br s. 1H), 2.71-2.73 (m, 2H), 1.71-1.74 (m, 2H)and 1.38 (s, 11H). MS: 346.18 (M+H)⁺. Yield: 96%.

General Method K:

To a solution of compound 8.30-e (1.0-2.0 g, 1.0 eq) in MeOH was addedammonium formate (5.0 eq) and Pd—C (w/w, 10 mol %) and the resultingsolution was stirred under at RT for 3-4 h. The reaction mixture wasfiltered through diatomaceous earth (Celite) bed and the filtrate wasconcentrated under reduced pressure to get the desired product 8.31-e.

Tert-butyl 4-((2-amino-5-cyanophenyl)amino)piperidine-1-carboxylate(8.31-e)

¹H-NMR (400 MHz, CDCl₃): δ 7.01 (d, J=8.8 Hz, 1H), 6.87 (s, 1H), 6.68(d, J=8.8 Hz, 1H), 4.05-4.10 (br s, 3H), 3.36-3.39 (m, 1H), 2.91-2.94(m, 2H), 2.00-2.03 (m, 4H) and 1.40 (s, 11H). MS: 317.39 (M+H)⁺. Yield:85%.

General Procedure for the Preparation of 8.32 (a-g):

General Method L:

To an ice-cold solution of compound 8.31 (a-g) (0.50-1.50 g, 1.0 eq) inTHF was added Et₃N (2.0 eq) and triphosgene (1.5 eq). The resultingreaction mixture was stirred at RT for 4 h. After completion of thereaction (TLC monitoring), the solvent was evaporated and the residuewas diluted with water and extracted with ethyl acetate (3 times). Thecombined organics were washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated. The crude was purified over silica gel(100-200 M, 30-40% EtOAc-hexane) to get the desired product 8.32 (a-g).

Tert-butyl4-(6,7-difluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate(8.32-a)

¹H-NMR (400 MHz, DMSO-d₆): δ 11.24 (br s, 1H), 7.02-7.06 (m, 1H),6.76-6.79 (m, 1H), 4.47-4.52 (m, 1H), 3.99-4.05 (m, 2H), 2.87-2.89 (m,2H), 1.90-1.98 (m, 2H), 1.71-1.74 (m, 2H) and 1.42 (s, 9H). LCMS: 354.55(M+H)⁺, 86.20%. Yield: 92%.

Tert-butyl4-(6-fluoro-2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate(8.32-b)

¹H-NMR (400 MHz, CDCl₃): δ 10.27 (br s, 1H), 7.17-7.21 (m, 1H),6.91-6.99 (m, 1H), 3.70-3.73 (m, 3H), 2.68-2.74 (m, 4H), 1.71-1.73 (m,2H) and 1.46 (s, 9H). LCMS: 354.55 (M+H)⁺, 86.20%. Yield: 72%.

Tert-butyl4-(6-fluoro-7-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate(8.32-c)

¹H-NMR (400 MHz, CDCl₃): δ 9.02 (br s, 1H), 6.75-6.82 (m, 2H), 4.49 (s,1H), 4.30-4.32 (m, 2H), 2.73 (s, 3H), 2.44-2.48 (m, 2H), 1.79-1.80 (m,2H), 1.60-1.62 (m, 2H) and 1.48 (s, 9H). LCMS: 350.36 (M+H)⁺, 90.82%.Yield: 80%.

Tert-butyl4-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidine-1-carboxylate(8.32-d)

LCMS: 319.33 (M+H)⁺, 87.69%. Yield: 85%.

Tert-butyl4-(6-cyano-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate(8.32-e)

¹H-NMR (400 MHz, CDCl₃): δ 10.01 (br s, 1H), 7.38-7.41 (m, 2H), 7.16 (d,J=8.0 Hz, 1H), 4.37-4.45 (m, 3H), 2.84-2.90 (m, 2H), 2.30-2.35 (m, 2H),1.83-1.85 (m, 2H) and 1.52 (s, 9H). LCMS: 343.37 (M+H)⁺, 86.18%. Yield:60%.

Tert-butyl4-(5-cyano-6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate(8.32-f)

¹H-NMR (400 MHz, CDCl₃): δ 9.87 (br s, 1H), 7.25-7.27 (m, 1H), 6.98 (d,J=8.8 Hz, 1H), 4.37-4.44 (m, 3H), 2.84-2.86 (m, 2H), 2.22-2.27 (m, 2H),1.84-1.84 (m, 2H) and 1.51 (s, 9H). LCMS: 359.11 (M−H)⁺, 98.18%. Yield:56%.

Tert-butyl4-(5,6,7-trifluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate(8.32-g)

¹H-NMR (400 MHz, DMSO-d₆): δ 11.28 (br s, 1H), 6.95-6.99 (m, 1H),4.47-4.50 (m, 1H), 3.99-4.05 (m, 2H), 2.86-2.89 (m, 2H), 1.90-1.98 (m,2H), 1.70-1.73 (m, 2H) and 1.42 (s, 9H). MS: 370.20 (M−H)⁺, Yield: 93%.

General Procedure for the Preparation of 8.33 (a-g):

General Method M:

An ice-cold solution of compound 8.32 (a-e) (0.5 g-1.0 g, 1.0 eq) indioxane-HCl (˜4N) was stirred at RT for 2 h. After completion of thereaction (TLC monitoring), the reaction mass was dried under reducedpressure. The crude was triturated with diethyl ether to get desiredproduct 8.33 (a-e) as off-white solids.

6,7-Difluoro-1-(piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-oneHydrochloride (8.33-a): Intermediate 16

¹H-NMR (400 MHz, DMSO-d₆): δ 11.38 (br s, 1H), 9.44 (br s, 1H), 8.65 (brs, 1H), 7.01-7.07 (m, 1H), 6.78-6.79 (m, 1H), 4.58-4.60 (m, 1H),3.63-3.65 (m, 2H), 2.45-3.49 (m, 2H), 3.03-3.12 (m, 2H) and 2.35-2.38(m, 2H). LCMS: 254.11 (M+H)⁺, 95.61%. Yield: quantitative.

6-Difluoro-1-(piperidin-4-yl)-7-(trifluoromethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-oneHydrochloride (8.33-b): Intermediate 17

¹H-NMR (400 MHz, DMSO-d₆): δ 11.66 (br s, 1H), 9.40 (br s, 1H), 8.57 (brs, 1H), 7.28-7.28 (m, 1H), 7.04-7.08 (m, 1H), 4.43-4.45 (m, 3H),2.82-2.90 (m, 4H) and 1.88-1.98 (m, 2H). LCMS: 304.21 (M+H)⁺, 92.41%.Yield: 92%.

6-Fluoro-7-methyl-1-(piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-oneHydrochloride (8.33-c): Intermediate 18

¹H-NMR (400 MHz, DMSO-d₆): δ 10.94 (br s, 1H), 9.44 (br s, 1H), 8.48 (brs, 1H), 6.76-6.83 (m, 2H), 4.44-4.48 (m, 1H), 3.32-3.38 (m, 2H),3.01-3.07 (m, 2H), 2.77-2.83 (m, 2H), 2.46 (s, 3H) and 1.93-1.96 (m,2H). MS: 250.29 (M+H)⁺. Yield: 93%.

3-(piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-oneHydrochloride (8.33-d): Intermediate 19

¹H-NMR (400 MHz, DMSO-d₆): δ 10.25 (br s, 1H), 9.36 (br s, 1H), 8.57 (brs, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.00 (t, J=7.6Hz, 1H), 4.55-4.61 (m, 1H), 3.35-3.38 (m, 2H), 3.03-3.11 (m, 2H),2.69-2.78 (m, 2H) and 1.86-1.89 (m, 2H). LCMS: 219.14 (M+H)⁺, 90.67%.Yield: 90%.

2-oxo-3-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrileHydrochloride (8.33-e): Intermediate 20

¹H-NMR (400 MHz, DMSO-d₆): δ 11.55 (br s, 1H), 8.93 (br s, 1H), 8.75 (brs, 1H), 7.86 (s, 1H), 7.47 (d, J=7.2 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H),4.57-4.60 (m, 1H), 3.35-3.40 (m, 2H), 3.04-3.08 (m, 2H), 2.55-2.61 (m,2H) and 1.85-1.88 (m, 2H). LCMS: 243.32 (M+H)⁺, 98.82%. Yield: 85%.

6-Fluoro-2-oxo-1-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrileHydrochloride (8.33-f)

¹H-NMR (400 MHz, DMSO-d₆): δ 11.49 (br s, 1H), 8.86 (br s, 2H),7.68-7.71 (m, 1H), 7.41-7.43 (s, 1H), 4.53-4.60 (m, 2H), 3.56-3.61 (m,1H), 3.04-3.16 (m, 2H), 2.55-2.58 (m, 2H) and 1.84-1.88 (m, 2H). LCMS:261.13 (M+H)⁺, 99.60%. Yield: 93%.

5,6,7-Trifluoro-1-(piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-oneHydrochloride (8.33-g)

Intermediate-6: ¹H-NMR (400 MHz, DMSO-d₆): δ 11.50 (br s, 1H), 9.26 (brs, 1H), 8.59-8.61 (m, 1H), 6.97-7.01 (m, 1H), 4.52-4.58 (m, 1H),3.25-3.40 (m, 2H), 3.07-3.13 (m, 2H), 2.33-2.41 (m, 2H) and 1.90-1.97(m, 2H). MS: 272.31 (M+H)⁺. Yield: 95%.

Preparation of 1-benzyl-2,6-dimethylpiperidin-4-one (9.35)

To an ice-cold solution of 3-oxopentanedioic acid 9.34 (10 g, 64.49mmol) in water (30 mL) was added acetaldehyde (6 g, 137 mmol) and benzylamine (7.50 mL, 64.49 mmol). The resulting yellow solution was stirredat RT for 78 h. After completion of reaction (TLC monitoring), cooledthe reaction mass, adjust pH˜2 using 1N HCl and stirred for 1 h at RT.The resulting mixture was neutralized with aq. NaHCO₃ solution andextracted with DCM (2×100 ml). Combined organics were washed with brine,dried with Na₂SO₄ and evaporated to get a brown liquid. The crude waspurified by flash chromatography using 10% EtOAc/hexane to get product9.35 (10 g, Yield: 68%) as a viscous liquid.

NMR (400 MHz, CDCl₃): δ 7.26-7.40 (m, 5H), 3.90-3.94 (m, 1H), 3.51-3.53(m, 1H), 3.24-3.30 (m, 2H), 2.42-2.51 (m, 2H), 2.12-2.21 (m, 2H) and1.05 (m, 6H). MS: 218.10 (M+H)⁺.

Preparation of 2,6-dimethylpiperidin-4-one (9.36)

To a solution of 1-benzyl-2,6-dimethylpiperidin-4-one 9.35 (8.0 g, 36.78mmol) in IPA (100 mL) was added Pd(OH)₂ (10% w/w, 0.8 g, 3.67 mmol). Theresulting mixture was stirred at RT for 16 h under H₂ atmosphere. Aftercompletion of reaction (TLC monitoring), reaction mass filtered throughdiatomaceous earth (Celite) bed, washed with EtOAc (100 mL). Thefiltrate was concentrated under reduced pressure to get desired product9.36 (3.6 g, Yield: 77%) as a viscous liquid. The crude was used for thenext step without purification. MS: 128.14 (M+H)⁺.

Preparation of tert-butyl 2,6-dimethyl-4-oxopiperidine-1-carboxylate(9.37)

To an ice-cold solution of 2,6-dimethylpiperidin-4-one 9.36 (3.6 g,28.34 mmol) in DCM (50 mL) was added Et₃N (9.8 mL, 70.8 mmol) and bocanhydride (12.1 mL, 56.6 mmol). The resulting reaction mixture wasstirred at RT for 16 h. After completion of the reaction (TLCmonitoring), the reaction mass was diluted with water and extracted withDCM (3 times). The combined organics were washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated. The crude was purified oversilica gel (100-200 M, 10-15% EtOAc-hexane) to get the desired product9.37 (3.9 g, Yield: 60.9%). ¹H-NMR (400 MHz, CDCl₃): δ 2.85 (d, J=6.4Hz, 1H), 2.81 (d, J=6.4 Hz, 1H), 2.38-2.39 (m, 2H), 2.34-2.36 (m, 2H),1.48 (s, 9H) and 1.25-1.27 (m, 6H). MS: 228.08 (M+H)⁺.

Preparation of tert-butyl4-(benzylamino)-2,6-dimethylpiperidine-1-carboxylate (9.38)

To an ice-cold solution of tert-butyl2,6-dimethyl-4-oxopiperidine-1-carboxylate 9.37 (3.4 g, 14.9 mmol) inDCM (50 mL) was added benzyl amine (2.13 mL, 17.9 mmol) and AcOH (1.02mL, 17.9 mmol). The resulting mixture was stirred at 0° C. for 2 hfollowed by addition of sodium tri-acetoxyborohydride (6.3 g, 29.8mmol). The resulting reaction mixture was stirred at RT for 16 h. Aftercompletion of the reaction (TLC monitoring), the reaction mass wasdiluted with water and extracted with DCM (3 times). The combinedorganics were washed with brine, dried over anhydrous Na₂SO₄, filteredand concentrated. The crude was purified over silica gel (100-200 M, 20%EtOAc-hexane) to get the desired product 9.38 (1.8 g, Yield: 37.8%). MS:319.34 (M+H)⁺.

Preparation of tert-butyl 4-amino-2,6-dimethylpiperidine-1-carboxylate(9.39)

Prepared following the general method F. MS: 229.20 (M+H)⁺. Yield:Quantitative.

Preparation of tert-butyl4-((2,3-difluoro-6-nitrophenyl)amino)-2,6-dimethylpiperidine-1-carboxylate(9.40)

Prepared following the general method I. ¹H-NMR (400 MHz, CDCl₃): δ7.95-8.04 (m, 2H), 6.47-6.54 (m, 1H), 4.30-4.35 (m, 2H), 3.88-3.89 (m,1H), 2.31-2.34 (m, 1H), 2.18-2.20 (m, 1H), 1.88-1.90 (m, 2H), 1.62 (s,9H) and 1.31-1.33 (m, 6H). MS: 386.31 (M+H)⁺. Yield: 35%.

Preparation of tert-butyl4-((6-amino-2,3-difluorophenyl)amino)-2,6-dimethylpiperidine-1-carboxylate(9.41)

Prepared following the general method J. ¹H-NMR (400 MHz, DMSO-d₆): δ6.57-6.64 (m, 1H), 6.34-6.36 (m, 1H), 4.78 (s, 2H), 4.16 (s, 1H),4.01-4.03 (m, 1H), 3.89-3.91 (m, 1H), 3.62 (br s, 1H), 1.88-1.89 (m,1H), 1.72-1.74 (m, 2H), 1.35-1.39 (m, 1H), 1.39 (s, 9H) and 1.31-1.33(m, 6H). MS: 356.38 (M+H)⁺. Yield: 35%.

Preparation of tert-butyl4-(6,7-difluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-2,6-dimethylpiperidine-1-carboxylate(9.42)

Prepared following the general method L. LCMS: 380.28 (M−H)⁺, 84.35%.Yield: 80%.

Preparation of1-(2,6-dimethylpiperidin-4-yl)-6,7-difluoro-1,3-dihydro-2H-benzo[d]imidazol-2-oneHydrochloride (9.43): Intermediate 21

Prepared following the general method M. ¹H-NMR (400 MHz, DMSO-d₆): δ11.33 (br s, 1H), 9.20-9.25 (m, 1H), 8.89-8.99 (m, 1H), 7.01-7.04 (m,1H), 6.75-6.78 (m, 1H), 4.73-4.79 (m, 1H), 3.61-3.64 (m, 2H), 3.35-3.38(m, 1H), 2.19-2.25 (m, 1H), 2.00-2.03 (m, 1H), 1.81-1.84 (m, 1H) and1.29-1.35 (m, 6H). LCMS: 280.13 (M−H)⁺, 84.65%. Yield: 90%.

Preparation of dimethyl 2,4-dimethyl-3-oxopentanedioate (10.2)

To an ice-cold solution of dimethyl 3-oxopentanedioate 10.1 (10.0 g,57.47 mmol) in THF (150 mL) was added K₂CO₃ (11.8 g, 86.2 mmol) andmethyl iodide (9.0 mL, 143.67 mmol). The resulting reaction mixture wasstirred at RT for 16 h. After completion of the reaction (TLCmonitoring), the reaction mass was diluted with water and extracted withDCM (3 times). The combined organics were washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated to get desired product 10.2(10.0 g, Yield: 86%) as viscous liquid. ¹H-NMR (400 MHz, CDCl₃): δ5.09-5.16 (m, 2H), 3.85-3.87 (m, 6H) and 3.51-3.54 (m, 6H). MS: 203.10(M+H)⁺.

Preparation of dimethyl1-benzyl-3,5-dimethyl-4-oxopiperidine-3,5-dicarboxylate (10.3)

To an ice-cold solution of dimethyl 2,4-dimethyl-3-oxopentanedioate 10.2(10.0 g, 49.3 mmol) in CH₃OH (100 mL) was added 1M-HCl (15.0 mL),benzylamine (5.4 mL, 49.3 mmol) and formaldehyde (37% in H₂O, 9.0 mL,108.46 mmol). The resulting reaction mixture was stirred at RT for 72 h.After completion of the reaction (TLC monitoring), the reaction mass wasdiluted with water and extracted with EtOAc (3 times). The combinedorganics were washed with brine, dried over anhydrous Na₂SO₄, filteredand concentrated to get desired product 10.3 (12.0 g, Yield: 73%) as aviscous liquid. The crude was used for the next step withoutpurification. MS: 334.18 (M+H)⁺.

Preparation of 1-benzyl-3,5-dimethylpiperidin-4-one (10.4)

A solution of dimethyl1-benzyl-3,5-dimethyl-4-oxopiperidine-3,5-dicarboxylate 10.3 (12.0 g,36.01 mmol) in 1N—HCl (100 mL) was heated at 100° C. for 16 h. Aftercompletion of the reaction (TLC monitoring), the reaction mass wascooled to 0° C., adjust pH˜10 using ammonium hydroxide solution andextracted with DCM (3 times). The combined organics were washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated to getdesired product 10.4 (7.5 g, Yield: quantitative) as viscous liquid. Thecrude was used for next step without purification. ¹H-NMR (400 MHz,CDCl₃): δ 7.32-7.35 (m, 5H), 3.64-3.66 (m, 2H), 3.10-3.13 (m, 2H),2.66-2.69 (m, 2H), 2.02-2.07 (m, 2H) and 0.95 (d, J=6.4 Hz, 6H). MS:203.10 (M+H)⁺.

Preparation of 1-benzyl-3,5-dimethylpiperidin-4-one Oxime (10.5)

To a solution of hydroxylamine hydrochloride (2.4 g, 34.56 mmol) in H₂O(30 mL) was added CH₃COONa (5.6 g, 69.12 mmol). The reaction mixture washeat at 60° C. and followed by addition of1-benzyl-3,5-dimethylpiperidin-4-one 10.4 (5.0 g, 23.04 mmol). Theresulting reaction mixture was heated at 60° C. for 2 h. Aftercompletion of the reaction (TLC monitoring), the reaction mass wascooled to RT and extracted with DCM (3 times). The combined organicswere washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated to get desired product 10.5 (5.0 g, Yield: quantitative).¹H-NMR (400 MHz, CDCl₃): δ 10.28 (s, 1H), 7.44-7.58 (m, 5H), 3.40-3.50(m, 2H), 3.20-3.22 (m, 2H), 2.56-2.59 (m, 2H), 2.03-2.10 (m, 2H) and1.17 (d, J=7.2 Hz, 6H). MS: 233.20 (M+H)⁺.

Preparation of 1-benzyl-3,5-dimethylpiperidin-4-amine (10.6)

To an ice-cold solution of 1-benzyl-3,5-dimethylpiperidin-4-one oxime10.5 (2.0 g, 8.62 mmol) was added LAH (2.0 M in THF, 13.0 mL). Theresulting reaction mixture was heated at 65° C. for 3 h. Aftercompletion of the reaction (TLC monitoring), the reaction mass wascooled to 0° C., added dropwise 15% NaOH solution (10 mL). The reactionmass was filtered through a diatomaceous earth (Celite) bed, and washedwith EtOAc (100 mL). The filtrate was dried over anhydrous Na₂SO₄,filtered and concentrated to get desired product 10.6 (1.4 g, Yield:70%). MS: 219.21 (M+H)⁺.

Preparation of1-benzyl-N-(2,3-difluoro-6-nitrophenyl)-3,5-dimethylpiperidin-4-amine(10.7)

This compound was prepared following the general Method I. ¹H-NMR (400MHz, CDCl₃): δ 8.02-8.05 (m, 1H), 7.38-7.50 (m, 5H), 6.44-6.51 (m, 1H),4.29-4.30 (m, 1H), 3.70-3.73 (m, 2H), 2.81-2.84 (m, 2H), 2.11-2.17 (m,2H), 1.55-1.57 (m, 2H), 1.31-1.32 (m, 1H) and 0.86 (d, J=6.4 Hz, 6H).LCMS: 376.06 (M+H)⁺, 96.22%. Yield: 25%.

Preparation ofN1-(1-benzyl-3,5-dimethylpiperidin-4-yl)-5,6-difluorobenzene-1,2-diamine(10.8)

This compound was prepared following the general Method J. LCMS: 344.39(M−H)⁺, 81.10%. Yield: 80%.

Preparation of1-(1-benzyl-3,5-dimethylpiperidin-4-yl)-6,7-difluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one(10.9)

This compound was prepared following the general Method L. MS: 370.36(M−H)⁺. Yield: 60%.

Preparation of1-(3,5-dimethylpiperidin-4-yl)-6,7-difluoro-1,3-dihydro-2H-benzo[d]imidazol-2-one(10.10): Intermediate 22

This compound was prepared following the general Method F. ¹H-NMR (400MHz, CDCl₃): δ 10.25 (br s, 1H), 7.02-7.09 (m, 1H), 6.75-6.79 (m, 1H),4.58 (br s, 1H), 3.48-3.51 (m, 2H), 3.38-3.40 (m, 2H), 3.00-3.02 (m,2H), 1.22-1.25 (m, 1H) and 0.80 (d, J=6.4 Hz, 6H). LCMS: 282.25 (M+H)⁺,88.77%. Yield: 90%.

Synthesis of Final Compounds

Preparation of 4-ethoxy-3,4-dioxo-1-(pyridin-3-yl)but-1-en-1-olateLithium Salt (11.3)

A solution of 3-acetyl pyridine 11.1 (20 g, 165.09 mmol) in di-ethylether (250 mL) was cooled to −78° C. followed by addition of LiHMDS (1.0M in THF, 181.60 mL, 181.60 mmol). The resulting reaction mixture wasstirred at −78° C. for 45 min followed by dropwise addition of diethyloxalate 11.2 (27.03 mL, 198.10 mmol) in about 20 min. The reactionmixture was then left to stir at room temperature for 16 h. Aftercompletion of the reaction (TLC and MS monitoring), the solution wasthen cooled to 0° C. and the resulting precipitate was filtered to getthe desired product 11.3 as an off-white solid (30 g), which was carriedforward to the next step without purification. ¹H-NMR (400 MHz,DMSO-d₆): δ 8.95 (s, 1H), 8.61 (d, J=4.0 Hz, 1H), 8.14 (m, 1H), 7.44 (m,1H), 6.40 (m, 1H), 4.12 (q, J=7.20 Hz, 2H) and 1.21 (t, J=7.2 Hz, 3H).MS: 221.95 (M+H)⁺. Yield: 82%.

Preparation of ethyl1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(11.5)

To an ice-cold solution of4-ethoxy-3,4-dioxo-1-(pyridin-3-yl)but-1-en-1-olate lithium salt 11.3(10 g, 45.23 mmol) in IPA (60 mL) was added(3-fluoro-4-(trifluoromethyl)phenyl)hydrazine hydrochloride 11.4 (10.5g, 54.28 mmol) and TFA (7.25 mL, 90.46 mL). The resulting reactionmixture was warmed to room temperature and then stirred at 90° C. for4-5 h. After completion of the reaction (TLC monitoring), the solventwas evaporated and the residue was diluted with water and extracted withethyl acetate (3 times). The combined organics were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated. Thecrude was purified over silica gel (100-200 M, 10-15% EtOAc-hexane) toget the desired product 11.5 (8.0 g, 47%). ¹H-NMR (400 MHz, CDCl₃): δ8.72 (m, 2H), 7.74 (m, 3H), 7.51 (d, J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz,1H), 7.15 (s, 1H), 4.48 (q, J=6.8 Hz, 2H) and 1.40 (t, J=7.2 Hz, 3H).MS: 379.90 (M+H)⁺.

Preparation of1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (11.6)

To an ice-cold solution of ethyl1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate11.5 (8.0 g, 21.09 mmol) in EtOH (60 mL) was added dropwise an aqueoussolution of sodium hydroxide (1.68 g, 42.18 mmol) in 8 mL H₂O. Theresulting solution was stirred at room temperature for 2 h. Aftercompletion of the reaction (TLC monitoring), the solvent was evaporated,added H₂O to the residue followed by extraction with EtOAc (2×100 mL).The organic layer was discarded and the pH of the aqueous layer wasadjusted to ˜4 by adding 1N HCl. The resulting precipitate was filteredand dried under vacuum to get the desired product 11.6 (4.5 g, 61%) as awhite solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 13.10 (br s, 1H), 8.59 (m,2H), 7.88 (t, J=8.0 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.65 (m, 1H), 7.45(m, 1H), 7.35 (d, J=8.4 Hz, 1H) and 7.26 (s, 1H). LCMS: 351.96 (M+H)⁺,93.37%.

General Procedure for the Preparation of Final Compounds (GeneralStructure 11.7):

General Method N:

To an ice-cold solution of1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicacid 11.6 (0.150 g, 0.43 mmol), in DMF (2.0 mL) was added DIPEA (2.5 eq)and HATU (1.50 eq). The resulting mixture was stirred under nitrogenatmosphere at 0° C. for 15 min followed by addition of respective amines(1.20 eq). The reaction mixture was then stirred at room temperature for16 h. After the completion of the reaction (TLC monitoring), thesolution was diluted with ice-cold water (30 mL) followed by extractionwith EtOAc (3×50 mL). The combined organics were washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude residue was purified via prep-HPLC.

Please refer to Table 6.1 for individual yields and the analytical dataof the final compounds.

TABLE 6.1 Tabulated data of the final compounds including the individualyields Amine intermediate Yield ¹H-NMR data (DMSO-d₆, 400 No. Structureused (%) LCMS MHz), unless otherwise specified 180

1 42 581.52 (M − H)⁺, 99.91% δ 8.81 (s, 1H), 8.59-8.62 (m, 2H), 7.83 (t,J = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.61-7.64 (m, 1H), 7.44-7.47(m, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.16 (s, 1H), 7.08-7.13 (m, 2H),6.86-6.88 (m, 2H), 4.48-4.62 (m, 2H), 4.43- 4.45 (m, 2H), 3.85-3.91 (m,1H), 3.51-3.57 (m, 1H), 2.20-2.24 (m, 2H) and 1.74-1.78 (m, 2H) 181

2 10 599.35 (M − H)⁺, 99.71% δ 8.89 (s, 1H), 8.60-8.62 (m, 2H), 7.82 (t,J = 8.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 7.2 Hz, 1H),7.44-7.47 (m, 1H), 7.28- 7.34 (m, 2H), 7.16 (s, 1H), 6.75- 6.79 (m, 1H),6.57-6.60 (m, 1H), 4.60 (s, 2H), 4.47-4.49 (m, 2H), 3.83-3.89 (m, 1H),3.50-3.55 (m, 1H), 2.32-2.40 (m, 2H) and 1.73- 1.82 (m, 2H) 182

Commercial 9 603.44 (M + H)⁺, 95.32% δ 8.61 (s, 2H), 7.82 (t, J = 8.64Hz, 1H), 7.73 (d, J = 7.68 Hz, 1H), 7.64 (m, 1H), 7.44-7.47 (m, 1H),7.33-7.35 (m, 1H), 7.24-7.31 (m, 2H), 7.19 (s, 1H), 6.99-7.01 (m, 1H),5.64 (s, 1H), 4.85-4.89 (m, 1H), 4.71-4.74 (m, 1H), 3.40 (s, 1H),2.05-2.09 (m, 2H) and 1.86 (s, 2H) 183

10 30 691.46 (M + H)⁺, 96.07% δ 8.87 (s, 1H), 8.62-8.63 (m, 2H), 7.82(t, J = 8.2 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.62- 7.64 (m, 1H),7.45-7.52 (m, 3H), 7.30 (d, J = 8.6 Hz, 1H), 7.08 (s, 1H), 6.59-6.61 (m,2H), 4.59-4.60 (m, 2H), 4.48-4.50 (m, 2H), 3.84-3.90 (m, 1H), 3.47-3.56(m, 1H), 2.38-2.42 (m, 2H) and 1.71-1.77 (m, 2H) 184

9 26 641.34 (M − H)⁺, 99.54% δ 8.88 (s, 1H), 8.61-8.62 (m, 2H), 7.84 (t,J = 8.24 Hz, 1H), 7.73 (d, J = 7.88 Hz, 1H), 7.62- 7.65 (m, 1H),7.44-7.48 (m, 1H), 7.36 (d, J = 8.76 Hz, 2H), 7.29 (d, J = 8.6 Hz, 1H),7.19 (s, 1H), 6.70-6.73 (m, 2H), 4.61 (s, 2H), 4.48-4.51 (m, 2H),3.84-3.90 (m, 1H), 3.51-3.57 (m, 1H), 2.42-2.49 (m, 2H) and 1.71-1.81(m, 2H) 185

15 18 595.34 (M − H)⁺, 99.29% δ 11.29 (br s, 1H), 8.60-8.62 (m, 1H),8.56 (d, J = 1.52 Hz, 1H), 7.84 (t, J = 8.28 Hz, 1H), 7.70 (d, J = 8.12Hz, 1H), 7.59 (d, J = 11.04 Hz, 1H), 7.44-7.48 (m, 1H), 7.27-7.37 (m,5H), 7.07 (s, 1H), 4.48-4.51 (m, 1H), 4.32- 4.36 (m, 1H), 3.78-3.84 (m,1H), 3.42-3.48 (m, 1H), 2.13- 2.22 (m, 2H) and 1.55-1.62 (m, 2H) 186

4 40 617.48 (M − H)⁺, 95.47% δ 8.95 (s, 1H), 8.63-8.64 (m, 2H), 7.85 (t,J = 8.24 Hz, 1H), 7.78-7.80 (m, 1H), 7.60-7.63 (m, 1H), 7.48-7.51 (m,1H), 7.27 (d, J = 8.76 Hz, 1H), 7.08 (s, 1H), 6.56-6.61 (m, 2H), 4.60(s, 2H), 4.47- 4.47 (m, 2H), 3.82-3.88 (m, 1H), 3.48-3.54 (m, 1H), 2.38-2.44 (m, 2H) and 1.73-1.81 (m, 2H) 187

5 18 651.54 (M − H)⁺, 95.32% δ 8.93 (s, 1H), 8.62-8.64 (m, 2H),7.82-7.86 (m, 1H), 7.75- 7.77 (m, 1H), 7.60-7.63 (m, 1H), 7.47-7.50 (m,1H), 7.38- 7.42 (m, 1H), 7.27-7.29 (m, 1H), 7.15 (s, 1H), 7.06-7.08 (m,1H), 6.94-6.97 (m, 1H), 4.68 (s, 2H), 4.47-4.51 (m, 2H), 3.75-3.80 (m,1H), 3.49- 3.55 (m, 1H), 2.32-2.41 (m, 2H) and 1.76-1.84 (m, 2H) 188

8 14 629.46 (M − H)⁺, 99.56% δ 8.84 (s, 1H), 8.60-8.63 (m, 2H), 7.82 (t,J = 8.28 Hz, 1H), 7.72 (d, J = 8.28 Hz, 1H), 7.61-7.64 (m, 1H),7.44-7.47 (m, 1H), 7.29-7.32 (m, 1H), 7.17 (s, 1H), 6.82-7.09 (m, 4H),4.61 (s, 2H), 4.46-4.49 (m, 2H), 3.85-3.91 (m, 1H), 3.51-3.57 (m, 1H),2.32-2.39 (m, 2H) and 1.74-1.82 (m, 2H) 189

3 8 617.26 (M + H)⁺, 93.55% δ 8.88 (s, 1H), 8.60-8.62 (m, 2H), 7.82 (t,J = 8.4 Hz, 1H), 7.72 (d, J = 7.88 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H),7.44- 7.47 (m, 1H), 7.28-7.32 (m, 2H), 7.16 (s, 1H), 6.85-6.89 (m, 1H),6.78-6.80 (m, 1H), 4.62 (s, 2H), 4.46-4.49 (m, 2H), 3.49- 3.55 (m, 2H),2.38-2.42 (m, 2H) and 1.74-1.79 (m, 2H) 190

20 13 574.46 (M − H)⁺, 99.75% δ 11.46 (br s, 1H), 8.62-8.64 (m, 2H),7.85-7.89 (m, 2H), 7.76 (d, J = 8.08 Hz, 1H), 7.64-7.67 (m, 1H),7.43-7.50 (m, 2H), 7.33 (d, J = 8.12 Hz, 1H), 7.18 (s, 1H), 7.10-7.12(m, 1H), 4.71-4.75 (m, 2H), 4.52-4.58 (m, 1H), 3.28-3.35 (m, 1H),2.90-2.97 (m, 1H), 2.29-2.36 (m, 2H) and 1.78-1.86 (m, 2H) 191

Commercial 30 476.43 (M + H)⁺, 99.89% δ 8.59-8.62 (m, 2H), 7.85 (t, J =8.08 Hz, 1H), 7.69-7.73 (m, 2H), 7.44-7.47 (m, 1H), 7.31 (d, J = 7.88Hz, 1H), 7.16 (s, 1H), 4.67-4.81 (m, 2H), 4.35- 4.42 (m, 1H), 4.01-4.07(m, 2H), 3.66-3.73 (m, 1H), 3.19- 3.21 (m, 1H), 3.08-3.12 (m, 1H) and2.78-2.84 (m, 1H) 192

Commercial 48 502.44 (M + H)⁺, 99.81% δ 8.59-8.63 (m, 2H), 7.87 (s, 1H),7.63-7.72 (m, 2H), 7.44- 7.47 (m, 1H), 7.29-7.34 (m, 1H), 7.16 (s, 1H),4.70-4.72 (m, 1H), 4.52-4.56 (m, 1H), 3.74-3.84 (m, 2H), 3.12-3.18 (m,2H), 2.85- 2.94 (m, 1H) and 0.94-1.08 (m, 4H) 193

11 5 609.52 (M + H)⁺, 99.73% δ 8.79 (br s, 1H), 8.63 (s, 2H), 7.81 (t, J= 8.4 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.57-7.60 (m, 1H), 7.45-7.48(m, 1H), 7.33 (s, 1H), 7.27-7.29 (m, 1H), 6.90-6.94 (m, 2H), 6.72-6.75(m, 2H), 5.24 (s, 1H), 4.92 (s, 1H), 4.54 (s, 2H), 3.31-3.33 (m, 2H),2.71-2.75 (m, 1H), 2.49-2.50 (m, 1H), 2.33-2.38 (m, 2H) and 1.82-1.92(m, 2H) 194

21 15 613.23 (M − H)⁺, 96.59% δ 11.25 (br s, 1H), 8.60-8.62 (m, 2H),8.58 (t, J = 8.4 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.60-7.63 (m, 1H),7.44-7.47 (m, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 7.00-7.06 (m,1H), 6.76-6.79 (m, 1H), 4.82 (s, 1H), 4.67 (s, 1H), 3.91 (s, 1H),2.22-2.27 (m, 2H), 1.88-1.91 (m, 1H), 1.78-1.81 (m, 1H), 1.52 (d, J =6.4 Hz, 3H) and 1.44 (d, J = 6.8 Hz, 3H) 195

6 20 609.18 (M − H)⁺, 99.41% δ 8.75 (s, 1H), 8.59-8.62 (m, 2H), 7.84 (t,J = 8.4 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.58- 7.61 (m, 1H), 7.41-7.47(m, 1H), 7.27 (d, J = 8.8 Hz, 1H), 7.12 (s, 1H), 6.58-6.59 (m, 2H), 4.55(s, 2H), 4.39 (s, 2H), 3.81- 3.87 (m, 2H), 2.28-2.32 (m, 1H), 2.18-2.21(m, 1H), 2.08 (s, 6H) and 1.72-1.80 (m, 2H) 196

17 35 635.45 (M − H)⁺, 99.92% δ 11.25 (br s, 1H), 8.60-8.62 (m, 2H),7.85 (t, J = 8.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.65-7.68 (m, 1H),7.44-7.47 (m, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.22-7.25 (m, 1H), 7.16 (s,1H), 7.04-7.09 (m, 1H), 4.82-4.85 (m, 1H), 4.70-4.73 (m, 1H), 4.21-4.27(m, 1H), 3.16-3.22 (m, 1H), 2.77-2.80 (m, 1H), 2.58-2.64 (m, 2H) and1.75-1.84 (m, 2H) 197

7 14 612.90 (M + H)⁺, 97.83% δ 8.59-8.60 (m, 1H), 8.56 (s, 1H), 8.50 (s,1H), 7.83 (t, J = 8.4 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.58-7.61 (m,1H), 7.42-7.45 (m, 1H), 7.27 (d, J = 6.4 Hz, 2H), 7.05 (s, 1H), 6.93-6.97 (m, 1H), 6.71-6.75 (m, 1H), 4.47-4.52 (m, 2H), 4.00- 4.08 (m, 1H),3.91-3.96 (m, 2H), 3.76 (s, 3H), 3.62-3.68 (m, 1H), 1.83-1.89 (m, 2H)and 1.40-1.46 (m, 2H)

Preparation of ethyl5-(pyridin-3-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carboxylate(12.2)

To an ice-cold solution of4-ethoxy-3,4-dioxo-1-(pyridin-3-yl)but-1-en-1-olate lithium salt 11.3(10.0 g, 45.23 mmol) in IPA (50 mL) was added(3,4,5-trifluorophenyl)hydrazine hydrochloride 12.1 (10.77 g, 54.28mmol) and TFA (6.9 mL, 90.46 mmol). The resulting reaction mixture waswarmed to room temperature and then stirred at 90° C. for 4 h. Aftercompletion of the reaction (TLC monitoring), the solvent was evaporatedand the residue was diluted with water and extracted with ethyl acetate(3 times). The combined organics were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated. The crude waspurified over silica gel (100-200 M, 10-15% EtOAc-hexane) to get thedesired product 12.2 (5.50 g, 35%). ¹H-NMR (400 MHz, CDCl₃): δ 8.68 (m,1H), 8.61 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.42 (m, 1H), 7.14 (s, 1H),7.03 (m, 2H), 4.48 (q, J=7.2 Hz, 2H) and 1.41 (t, J=7.2 Hz, 3H). MS:348.15 (M+H)⁺.

Preparation of5-(pyridin-3-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carboxylic Acid(12.3)

To an ice-cold solution of ethyl5-(pyridin-3-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carboxylate12.2 (5.50 g, 15.82 mmol) in EtOH (40 mL) was added dropwise an aqueoussolution of sodium hydroxide (1.26 g, 31.64 mmol). The resultingsolution was stirred at room temperature for 2 h. After completion ofthe reaction (TLC monitoring), the solvent was evaporated, added H₂O tothe residue followed by extraction with EtOAc (2×100 mL). The organiclayer was discarded and the pH of the aqueous layer was adjusted to ˜4by adding 1N HCl. The resulting precipitate was filtered and dried undervacuum to get the desired product 12.3 (3.0 g, 59%) as a white solid.¹H-NMR (400 MHz, DMSO-d₆): δ 13.13 (br s, 1H), 8.59 (s, 2H), 7.65 (d,J=8.4 Hz, 1H), 7.52 (m, 2H), 7.41 (m, 1H) and 7.25 (s, 1H). LCMS: 320.14(M+H)⁺, 95.20%.

General Procedure for the Preparation of Final Compounds (GeneralStructure 12.4):

The final compounds were prepared following the general method N. To anice-cold solution of carboxylic acid 12.3 (125-150 mg), in DMF (2.0 mL)was added DIPEA (2.5 eq) and HATU (1.50 eq). The resulting mixture wasstirred under nitrogen atmosphere at 0° C. for 15 min followed byaddition of respective amines (1.20 eq). The reaction mixture was thenstirred at room temperature for 16 h. After the completion of thereaction (TLC monitoring), the solution was diluted with ice-cold water(30 mL) followed by extraction with EtOAc (3×50 mL). The combinedorganics were washed with brine, dried over anhydrous Na₂SO₄, filteredand concentrated under reduced pressure. The crude residue was purifiedvia prep-HPLC.

Please refer to Table 6.2 for individual yields and the analytical dataof the final compounds.

TABLE 6.2 Tabulated data of the final compounds including the individualyields Amine Intermediate Yield No. Structure used (%) LCMS NMR data(DMSO-d₆, 400 MHz) 198

16 32 555.11 (M + H)⁺, 95.55% δ 11.25 (br s, 1H), 8.60 (s, 2H), 7.67 (d,J = 8.0 Hz, 1H), 7.50- 7.53 (m, 2H), 7.39-7.42 (m, 1H), 7.14 (s, 1H),7.00-7.05 (m, 1H), 6.77-6.80 (m, 1H), 4.80-4.84 (m, 1H), 4.67-4.70 (m,2H), 3.32 (s, 1H), 2.92-2.98 (m, 1H), 2.11-2.16 (m, 2H) and 1.85-1.88(m, 2H) 199

Commercial 10 569.31 (M − H)⁺, 88.55% δ 13.11 (br s, 1H), 8.60 (s, 2H),7.70 (d, J = 8.56 Hz, 1H), 7.50- 7.53 (m, 2H), 7.41-7.44 (m, 1H),7.24-7.29 (m, 1H), 7.16 (s, 1H), 7.00-7.01 (m, 1H), 4.87-4.90 (m, 1H),4.72-4.74 (m, 2H), 3.32 (s, 1H), 2.92-2.98 (m, 1H), 2.07-2.11 (m, 2H)and 1.86-1.90 (m, 2H) 200

10 22 659.50 (M + H)⁺, 97.37% δ 8.87 (s, 1H), 8.62-8.63 (m, 2H), 7.71(t, J = 8.2 Hz, 1H), 7.44-7.51 (m, 5H), 7.17 (s, 1H), 6.58-6.60 (m, 2H),4.59-4.60 (m, 2H), 4.49-4.50 (m, 2H), 3.82-3.87 (m, 2H), 3.49-3.55 (m,1H), 2.42-2.45 (m, 1H) and 1.70-1.79 (m, 2H) 201

9 25 609.29 (M − H)⁺, 99.91 δ 8.88 (s, 1H), 8.60-8.61 (m, 2H), 7.66 (t,J = 8.04 Hz, 1H), 7.36-7.50 (m, 5H), 7.17 (s, 1H), 6.69-6.72 (m, 2H),4.59-4.60 (m, 2H), 4.47-4.50 (m, 2H), 3.82-3.88 (m, 1H), 3.50-3.55 (m,1H), 2.42-2.49 (m, 2H) and 1.70-1.80 (m, 2H) 202

18 18 551.37 (M + H)⁺, 99.88% δ 10.84 (br s, 1H), 8.60 (s, 2H), 7.68 (t,J = 7.92 Hz, 1H), 7.50-7.56 (m, 2H), 7.42-7.45 (m, 1H), 7.13 (s, 1H),6.74-6.82 (m, 2H), 4.76-4.79 (m, 1H), 4.66- 4.69 (m, 2H), 3.25-3.28 (m,1H), 2.88-2.94 (m, 1H), 2.55-2.58 (m, 2H), 2.50 (s, 3H) and 1.84-1.90(m, 2H) 203

21 5 583.21 (M + H)⁺, 97.96% δ 11.25 (br s, 1H), 8.59-8.60 (m, 2H), 7.67(d, J = 8.0 Hz, 1H), 7.47-7.50 (m, 2H), 7.41-7.44 (m, 1H), 7.10 (s, 1H),7.00-7.07 (m, 1H), 6.76-6.79 (m, 1H), 4.80 (s, 1H), 4.67 (s, 1H), 3.90(s, 1H), 2.23-2 30 (m, 2H), 1.80-1.90 (m, 2H), 1.51 (d, J = 6.4 Hz, 3H)and 1.42 (d, J = 6.8 Hz, 3H) 204

6 18 579.13 (M + H)⁺, 99.12% δ 8.74 (s, 1H), 8.58-8.60 (m, 2H), 7.66 (d,J = 8.0 Hz, 1H), 7.41-7.48 (m, 3H), 7.10 (s, 1H), 6.58-6.59 (m, 2H),4.55 (s, 2H), 4.38-4.41 (s, 2H), 3.79-3.85 (m, 1H), 3.47- 3.53 (m, 1H),2.21-2.25 (m, 2H), 2.12 (s, 6H) and 1.72-1.79 (m, 2H) 207

22 6 583.37 (M + H)⁺, 97.90% δ 11.31 (br s, 1H), 8.60-8.61 (m, 2H), 7.69(d, J = 8.4 Hz, 1H), 7.43-7.52 (m, 3H), 7.10 (s, 1H), 6.99-7.07 (m, 1H),6.77-6.79 (m, 1H), 4.65 (s, 1H), 431-4.34 (m, 2H), 3.87-3.90 (m, 1H),3.51- 3.54 (m, 1H), 2.26-2.33 (m, 2H), 0.85 (d, J = 6.4 Hz, 3H) and 0.77(d, J = 6.8 Hz, 3H) 208

19 12 518.13 (M − H)⁺, 97.02% δ 11.12 (br s, 1H), 8.59-8.60 (m, 2H),7.92 (d, J = 4.4 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.50- 7.54 (m, 2H),7.41-7.44 (m, 1H), 7.28 (d J = 6.8 Hz, 1H), 7.15 (s, 1H), 6.97 (t, J =7.6 Hz, 1H), 4.79-4.82 (m, 1H), 4.69-4.72 (m, 1H), 4.55-4.57 (m, 1H),3.28- 3.32 (m, 1H), 2.90-2.96 (m, 1H), 2.50-2.55 (m, 2H) and 1.76-1.84(m, 2H)

Preparation of Ethyl4-bromo-5-(pyridin-3-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carboxylate(13.1)

To a solution of ethyl5-(pyridin-3-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carboxylate12.2 (1.0 g, 2.88 mmol) in DMF (15 mL) was added NBS (0.77 g, 4.32mmol). The resulting reaction mixture was heated at 50° C. for 4 h.After completion of the reaction (TLC monitoring), the solvent wasice-cold water and extracted with ethyl acetate (3 times). The combinedorganics were washed with ice-cold water, brine, dried over anhydroussodium sulfate, filtered and concentrated. The crude was purified oversilica gel (100-200 M, 3-5% EtOAc-hexane) to get the desired product13.1 (0.99 g, yield: 81%). ¹H-NMR (400 MHz, CDCl₃): δ 8.71-8.72 (m, 1H),8.53 (s, 1H), 7.66 (d, J=7.88 Hz, 1H), 7.42-7.45 (m, 1H), 6.93-6.99 (m,2H), 4.50 (q, J=7.12 Hz, 2H) and 1.39 (t, J=7.2 Hz, 3H). MS: 426.18(M+H)⁺.

4-Bromo-5-(pyridin-3-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carboxylicAcid (13.2)

To an ice-cold solution of ethyl4-bromo-5-(pyridin-3-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carboxylate13.1 (0.99 g, 2.33 mmol) in EtOH (20 mL) was added dropwise an aqueoussolution of sodium hydroxide (0.19 g, 4.66 mmol). The resulting solutionwas stirred at room temperature for 2 h. After completion of thereaction (TLC monitoring), the solvent was evaporated, added H₂O to theresidue followed by extraction with EtOAc (2×100 mL). The organic layerwas discarded and the pH of the aqueous layer was adjusted to ˜4 byadding 1N HCl. The resulting precipitate was filtered and dried undervacuum to get the desired product 13.2 (0.35 g, yield: 39%) as a whitesolid. ¹H-NMR (400 MHz, DMSO-d₆): δ 13.45 (br s, 1H), 8.64-8.65 (m, 1H),8.57 (s, 1H), 7.77 (d, J=7.96 Hz, 1H) and 7.48-7.52 (m, 3H). LCMS:397.94 (M+H)⁺, 86.45%.

General Procedure for the Preparation of Final Compounds (GeneralStructure 13.3):

The final compounds were prepared following the general method N on100-150 mg scale. Please refer to Table 6.3 for individual yields andthe analytical data of the final compounds.

TABLE 6:3 Tabulated data of the final compounds including the individualyields Amine Iintermediate Yield No. Structure Used (%) LCMS NMR data(DMSO-d₆, 400 MHz) 210

1 13 629.42 (M + H)⁺, 99.53% δ 8.84 (s, 1H), 8.65-8.66 (m, 1H), 8.58 (s,1H), 7.77 (d, J = 7.84 Hz, 1H), 7.50-7.53 (m, 1H), 7.42- 7.45 (m, 2H),7.10-7.14 (m, 2H), 6.83-6.86 (m, 2H), 4.58-4.61 (m, 2H), 4.45-4.48 (m,1H), 3.80- 3.90 (m, 2H), 3.52-3.58 (m, 1H), 2.27-2.32 (m, 2H), 1.80-1.84(m, 1H) and 1.71-1.75 (m, 1H) 211

16 26 633.38 (M + H)⁺, 97.73% δ 10.50 (br s, 1H), 8.65-8.66 (m, 1H),8.59 (s, 1H), 7.78 (d, J = 7.88 Hz, 1H), 7.44-7.52 (m, 3H), 7.00-7.07(m, 1H), 6.78- 6.80 (m, 1H), 4.60-4.70 (m, 2H), 4.10-4.13 (m, 1H), 3.32(s, 1H), 2.97-3.03 (m, 1H), 2.12-2.18 (m, 2H) and 1.75-1.90 (m, 2H)

General Procedure for the Preparation of Compounds 14.1 (a-l):

To an ice-cold solution of4-ethoxy-2-methyl-3,4-dioxo-1-(pyridin-3-yl)but-1-en-1-olate lithiumsalt 11.3 (3.0 g, 13.21 mmol) in IPA was added respective hydrazinehydrochloride (1.2 eq) and TFA (2.0 eq). The resulting reaction mixturewas warmed to room temperature and then stirred at 90° C. for 4-5 h.After completion of the reaction (TLC monitoring), the solvent wasevaporated and the residue was diluted with water and extracted withethyl acetate (3 times). The combined organics were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated. Thecrude was purified over silica gel (100-200 M, 10-15% EtOAc-hexane) toget the desired product 14.1 (a-l).

Ethyl 1-(4-cyanophenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(14.1-a)

¹H-NMR (400 MHz, CDCl₃): δ 9.17 (m, 1H), 8.80-8.81 (m, 1H), 8.22-8.24(m, 1H), 7.61-7.63 (m, 2H), 7.42-7.45 (m, 2H), 7.14 (s, 1H), 7.05-7.09(m, 1H), 4.44 (q, J=7.2 Hz, 2H) and 1.35 (t, J=7.2 Hz, 3H). MS: 319.03(M+H)⁺. Yield: 13%.

Ethyl1-(3-fluoro-4-(trifluoromethoxy)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(14.1-b)

¹H-NMR (400 MHz, CDCl₃): δ 8.62-8.68 (m, 2H), 7.61-7.63 (m, 1H),7.41-7.44 (m, 1H), 7.29-7.34 (m, 2H), 7.14 (s, 1H), 7.07-7.10 (m, 1H),4.44 (q, J=7.6 Hz, 2H) and 1.38 (t, J=7.2 Hz, 3H). MS: 396.14 (M+H)⁺.Yield: 41%.

Ethyl1-(4-cyano-3-fluorophenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(14.1-c)

¹H-NMR (400 MHz, CDCl₃): δ 8.71-8.72 (m, 1H), 8.62 (s, 1H), 7.61-7.64(m, 2H), 7.44-7.47 (m, 1H), 7.35-7.38 (m, 1H), 7.19 (s, 1H), 7.15-7.17(m, 1H), 4.42 (q, J=7.6 Hz, 2H) and 1.36 (t, J=7.6 Hz, 3H). LCMS: 337.13(M+H)⁺, 96.65%. Yield: 26%.

Ethyl1-(4-(tert-butyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(14.1-d)

¹H-NMR (400 MHz, CDCl₃): δ 8.58-8.62 (m, 1H), 8.54-8.58 (m, 1H),7.52-7.54 (m, 1H), 7.39-7.41 (m, 2H), 7.22-7.28 (m, 3H), 7.11 (s, 1H),4.44 (q, J=7.2 Hz, 2H), 1.37 (t, J=7.6 Hz, 3H) and 1.25 (s, 9H). MS:350.23 (M+H)⁺. Yield: 23%.

Ethyl1-(2-chloro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(14.1-e)

¹H-NMR (400 MHz, CDCl₃): δ 8.57-8.58 (m, 1H), 8.48 (s, 1H), 7.65-7.70(m, 3H), 7.48-7.50 (m, 1H), 7.24-7.27 (m, 1H), 7.14 (s, 1H), 4.44 (q,J=7.2 Hz, 2H) and 1.36 (t, J=7.2 Hz, 3H). MS: 396.27 (M+H)⁺. Yield: 30%.

Ethyl1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(14.1-f)

¹H-NMR (400 MHz, CDCl₃): δ 8.71-8.76 (m, 1H), 8.62-8.65 (m, 1H), 7.74(d, J=8.0 Hz, 1H), 7.69 (s, 2H), 7.46-7.49 (m, 1H), 7.21 (s, 1H), 4.45(q, J=7.6 Hz, 2H) and 1.38 (t, J=7.2 Hz, 3H). MS: 430.08 (M+H)⁺. Yield:31%.

Ethyl5-(pyridin-3-yl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazole-3-carboxylate(14.1-g)

¹H-NMR (400 MHz, CDCl₃): δ 8.73-8.81 (m, 2H), 8.39-8.41 (m, 1H),7.72-7.74 (m, 1H), 7.52-7.54 (m, 1H), 7.45-7.47 (m, 2H), 7.33-7.35 (m,2H), 4.52 (q, J=7.6 Hz, 2H) and 1.51 (t, J=7.2 Hz, 3H). LC-MS: 378.28(M+H)⁺, 88.27% Yield: 40%.

Ethyl1-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(14.1-h)

¹H-NMR (400 MHz, CDCl₃): δ 8.59-8.66 (m, 1H), 7.77-7.78 (m, 1H), 7.56(d, J=8.04 Hz, 1H) 7.38-7.41 (m, 2H), 7.23-7.25 (m, 1H), 7.21 (s, 1H),7.07-7.10 (m, 1H), 4.48 (q, J=7.2 Hz, 2H) and 1.38 (t, J=7.6 Hz, 3H).MS: 380.22 (M+H)⁺. Yield: 35%.

Ethyl1-(2,3-difluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(14.1-i)

¹H-NMR (400 MHz, CDCl₃): δ 8.75-8.79 (m, 1H), 8.50-8.51 (m, 1H),7.52-7.57 (m, 3H), 7.26 (s, 1H), 7.15 (s, 1H), 4.44 (q, J=6.92 Hz, 2H)and 1.39 (t, J=7.16 Hz, 3H). MS: 397.94 (M+H)⁺. Yield: 16%.

Ethyl1-(2,5-difluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(14.1-j)

¹H-NMR (400 MHz, CDCl₃): δ 8.66-8.73 (m, 2H), 7.80 (d, J=8.0 Hz, 1H),7.62-7.66 (m, 1H), 7.55-7.58 (m, 1H), 7.35-7.35 (m, 1H), 7.21 (s, 1H),4.48 (q, J=7.20 Hz, 2H) and 1.42 (t, J=7.20 Hz, 3H). MS: 398.15 (M+H)⁺.Yield: 35%.

Ethyl1-(4-cyano-3-fluorophenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(14.1-k)

¹H-NMR (400 MHz, CDCl₃): δ 8.71-8.72 (m, 1H), 8.62 (s, 1H), 7.61-7.64(m, 2H), 7.44-7.47 (m, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.26 (s, 1H),7.15-7.17 (m, 1H), 4.50 (q, J=7.16 Hz, 2H) and 1.43 (t, J=7.24 Hz, 3H).MS: 337.14 (M+H)⁺. Yield: 26%.

Ethyl1-(2-methyl-4-(trifluoromethoxy)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(14.1-l)

¹H-NMR (400 MHz, CDCl₃): δ 8.51-8.55 (m, 2H), 8.40-8.42 (m, 1H),7.32-7.34 (m, 1H), 7.20-7.24 (m, 1H), 7.17 (s, 1H), 6.94-6.99 (m, 2H),4.43 (q, J=7.20 Hz, 2H), 1.98 (s, 3H) and 1.42 (t, J=7.24 Hz, 3H). MS:392.54 (M+H)⁺. Yield: 29%.

General Procedure for the Preparation of Compounds 14.2 (a-l):

To an ice-cold solution of compound 14.1 (a-l) (0.80-1.5 g, 1.0 eq) inEtOH was added dropwise an aqueous solution of sodium hydroxide (3.0eq). The resulting solution was stirred at room temperature for 2-3 h.After completion of the reaction (TLC monitoring), the solvent wasevaporated, added H₂O to the residue followed by extraction with EtOAc(2×100 mL). The organic layer was discarded and the pH of the aqueouslayer was adjusted to ˜4 by adding 1N HCl. The resulting precipitate wasfiltered and dried under vacuum to get the desired product 69 (a-l) as awhite solid.

1-(4-Cyanophenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylic Acid(14.2-a)

LC-MS: 291.27 (M+H)⁺, 85.5%. Yield: 66%.

1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (14.2-b)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.15 (br s, 1H), 8.56-8.59 (m, 2H),7.68-7.71 (m, 3H), 7.41-7.44 (m, 1H), 7.25-7.29 (m, 1H) and 7.17 (s,1H). LCMS: 368.29 (M+H)+, 94.25%. Yield: 61%.

1-(4-Cyano-3-fluorophenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (14.2-c)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.18 (br s, 1H), 8.59-8.91 (m, 2H),7.67-7.68 (m, 2H), 7.41-7.44 (m, 1H), 7.25-7.27 (m, 2H) and 7.22 (s,1H). MS: 309.11 (M+H)⁺. Yield: 30%.

1-(4-(tert-Butyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylic Acid(14.2-d)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.0 (br s, 1H), 8.54-8.55 (m, 1H), 8.48(s, 1H), 7.66-7.68 (m, 1H), 7.47-7.49 (m, 2H), 7.39-7.42 (m, 1H),7.26-7.28 (m, 2H), 7.20 (s, 1H) and 1.29 (s, 9H). LCMS: 322.0 (M+H)⁺,98.33%. Yield: 30%.

1-(2-Chloro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (14.2-e)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.19 (br s, 1H), 8.50-8.54 (m, 2H), 8.14(s, 1H), 8.04 (d, J=8.16 Hz, 1H), 7.96 (d, J=8.20 Hz, 1H), 7.62-7.63 (m,1H), 7.37-7.43 (m, 1H) and 7.33 (s, 1H). LCMS: 368.12 (M+H)⁺, 97.38%.Yield: 81%.

1-(2,6-Dichloro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (14.2-f)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.33 (br s, 1H), 8.57 (d, J=1.6 Hz, 1H),8.52 (s, 1H), 8.28 (s, 2H), 7.60-7.62 (m, 1H) and 7.41-7.44 (m, 2H).LCMS: 402.08 (M+H)⁺, 96.28%. Yield: 84%.

5-(Pyridin-3-yl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazole-3-carboxylicAcid (14.2-g)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.09 (br s, 1H), 8.52-8.57 (m, 2H),7.66-7.70 (m, 1H), 7.40-7.43 (m, 5H) and 7.23 (s, 1H). LCMS: 350.27(M+H)⁺, 91.79%. Yield: 63%.

1-(4-Fluoro-3-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (14.2-h)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.15 (br s, 1H), 8.57-8.58 (m, 2H),7.84-7.86 (m, 1H), 7.60-7.69 (m, 3H), 7.40-7.45 (m, 1H) and 7.24 (s,1H). LCMS: 352.24 (M+H)+, 95.84%. Yield: 73%.

1-(2,3-Difluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (14.2-i)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.30 (br s, 1H), 8.60-8.61 (m, 2H),7.80-7.83 (m, 1H), 7.63-7.73 (m, 2H), 7.41-7.44 (m, 1H) and 7.25 (s,1H). MS: 370.08 (M+H)⁺, Yield: 86%.

1-(2,5-Difluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (14.2-j)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.34 (br s, 1H), 8.60 (s, 2H), 7.99-8.10(m, 2H), 7.72 (d, J=7.0 Hz, 1H), 7.43 (s, 1H) and 7.33 (s, 1H). LCMS:370.27 (M+H)+, 97.55%. Yield: 68%.

1-(4-Cyano-3-fluorophenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (14.2-k)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.18 (br s, 1H), 8.59 (s, 2H), 8.01-8.05(m, 1H), 7.81 (d, J=8.32 Hz, 1H), 7.67-7.70 (m, 2H), 7.25-7.27 (m, 1H)and 7.22 (s, 1H). MS: 309.11 (M+H)⁺. Yield: 30%.

1-(2-Methyl-4-(trifluoromethoxy)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (14.2-1)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.08 (br s, 1H), 8.51-8.57 (m, 1H), 8.47(s, 1H), 7.55-7.62 (m, 2H), 7.44 (s, 1H), 7.34-7.38 (m, 2H), 7.29 (s,1H) and 1.93 (s, 3H). LCMS: 364.26 (M+H)⁺, 92.06%. Yield: 75%.

General Procedure for the Preparation of Final Compounds (GeneralStructure 14.3)

The final compounds were prepared following the general method N. To anice-cold solution of carboxylic acids 14.2 (a-l) (125-150 mg), in DMF(2.0 mL) was added DIPEA (2.5 eq) and HATU (1.50 eq). The resultingmixture was stirred under nitrogen atmosphere at 0° C. for 15 minfollowed by addition of respective amines (1.20 eq). The reactionmixture was then stirred at room temperature for 16 h. After thecompletion of the reaction (TLC monitoring), the solution was dilutedwith ice-cold water (30 mL) followed by extraction with EtOAc (3×50 mL).The combined organics were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The finalcompounds were purified via prep-HPLC.

Please refer to Table 6.4 for individual yields and the analytical dataof the final compounds.

TABLE 6.4 Tabulated data of the final compounds including the individualyields Amine intermediate Yield No. Structure used (%) LCMS NMR data(DMSO-d₆, 400 MHz) 212

16 15 524.35 (M − H)⁺, 99.78% δ 11.15 (br s, 1H), 8.60 (d, J = 1.12 Hz,1H), 8.56 ((d, J = 1.68 Hz, 1H), 7.93 (d, J = 8.52 Hz, 2H), 7.68 ((d, J= 8.0 Hz, 1H), 7.54 ((d, J = 8.52 Hz, 2H), 7.41- 7.45 (m, 1H), 7.15 (s,1H), 7.00- 7.07 (m, 1H), 6.77-6.80 (m, 1H), 4.80-4.83 (m, 1H), 4.63-4.71(m, 2H), 3.32 (s, 1H), 2.93-2.99 (m, 1H), 2.07-2.17 (m, 2H) and1.85-1.88 (m, 2H) 213

2 13 538.35 (M − H)⁺, 98.24% δ 8.89 (s, 1H), 8.56-8.61 (m, 2H), 7.91 (t,J = 8.52 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.12 Hz, 1H),7.51-7.54 (m, 2H), 7.42-7.45 (m, 1H), 7.26-7.31 (m, 1H), 7.15 (s, 1H),6.74-6.79 (m, 1H), 6.57-6.59 (m, 1H), 4.59 (s, 2H), 4.47-4.52 (m, 2H),3.84-3.90 (m, 1H), 3.49-3.55 (m, 1H), 2.35-2.39 (m, 2H) and 1.73-1.81(m, 2H) 214

2 31 615.38 (M − H)⁺, 99.36% δ 8.88 (s, 1H), 8.58-8.61 (m, 2H),7.63-7.72 (m, 3H), 7.47- 7.47 (m, 1H), 7.24-7.34 (m, 2H), 7.15 (s, 1H),6.74-6.79 (m, 1H), 6.57-6.59 (m, 1H), 4.60 (s, 2H), 4.47-4.52 (m, 2H),3.83-3.89 (m, 1H), 3.45-3.55 (m, 1H), 2.33-2.44 (m, 2H) and 1.73-1.77(m, 2H) 215

16 22 603.42 (M + H)⁺, 96.04% δ 11.25 (br s, 1H), 8.57-8.59 (m, 2H),7.68-7.72 (m, 3H), 7.42- 7.45 (m, 1H), 7.28 (d, J = 8.6 Hz, 1H), 7.14(s, 1H), 7.00- 7.04 (m, 1H), 6.77-6.80 (m, 1H), 4.82-4.85 (m, 1H),4.67-4.71 (m, 2H), 3.32 (s, 1H), 2.92-2.98 (m, 1H), 2.11-2.17 (m, 2H)and 1.85-1.92 (m, 2H) 216

2 6 556.41 (M − H)⁺, 99.04% δ 8.89 (s, 1H), 8.61-8.63 (m, 2H), 7.97 (d,J = 7.92 Hz, 1H), 7.71 (d, J = 7.92 Hz, 1H), 7.62- 7.65 (m, 1H),7.43-7.47 (m, 1H), 7.28-7.33 (m, 2H), 7.17 (s, 1H), 6.74-6.78 (m, 1H),6.57-6.59 (m, 1H), 4.60 (s, 2H), 4.45-4.49 (m, 2H), 3.83-3.89 (m, 1H),3.50-3.55 (m, 1H), 2.36-2.43 (m, 2H) and 1.73- 1.82 (m, 2H) 217

2 27 571.51 (M + H)⁺, 99.10% δ 8.87 (s, 1H), 8.51-8.57 (m, 2H), 7.70 (d,J = 8.0 Hz, 1H), 7.43-7.46 (m, 3H), 7.20-7.26 (m, 3H), 7.11 (s, 1H),6.74-6.78 (m, 1H), 6.56-6.59 (m, 1H), 4.59 (s, 3H), 4.47-4.49 (m, 1H),3.78-3.82 (m, 1H), 3.48-3.54 (m, 1H), 2.38-2.40 (m, 2H), 1.72- 1.80 (m,2H) and 1.27 (s, 9H) 218

2 40 617.47 (M + H)⁺, 99.59% δ 8.87 (s, 1H), 8.54 (d, J = 4.44 Hz, 1H),8.50 (s, 1H), 8.13 (s, 1H), 7.96-7.98 (m, 1H), 7.90- 7.92 (m, 1H),7.61-7.63 (m, 1H), 7.38-7.41 (m, 1H), 7.23- 7.27 (m, 2H), 6.71-6.76 (m,1H), 6.54-6.56 (m, 1H), 4.58 (s, 2H), 4.47-4.50 (m, 2H), 3.81-3.87 (m,1H), 3.49-3.54 (m, 1H), 2.32-2.40 (m, 2H) and 1.70-1.81 (m, 2H) 219

2 42 649.35 (M − H)⁺, 98.81% δ 8.87 (s, 1H), 8.57 (d, J = 4.16 Hz, 1H),8.52 (s, 1H), 8.24 (d, J = 7.56 Hz, 2H), 7.60-7.62 (m, 1H), 7.41-7.44(m, 1H), 7.28 (s, 1H), 7.21-7.25 (m, 1H), 6.71- 6.75 (m, 1H), 6.53-6.55(m, 1H), 4.58 (s, 2H), 4.46-4.49 (m, 1H), 4.46-4.54 (m, 1H), 3.80- 3.86(m, 1H), 3.49-3.54 (m, 1H), 2.32-2.40 (m, 2H) and 1.69-1.81 (m, 2H) 220

16 58 583.39 (M − H)⁺, 99.73% δ 11.18 (br s, 1H), 8.56 (d, J = 4.08 Hz,1H), 8.54 (s, 1H), 7.67 (d, J = 7.84 Hz, 1H), 7.40-7.52 (m, 5H), 7.13(s, 1H), 6.99-7.06 (m, 1H), 6.77-6.80 (m, 1H), 4.85-4.89 (m, 1H),4.65-4.71 (m, 2H), 3.31 (s, 1H), 2.92-2.98 (m, 1H), 2.07-2.17 (m, 2H)and 1.84-1.91 (m, 2H) 221

1 23 581.12 (M − H)⁺, 98.65% δ 8.80 (s, 1H), 8.57 (s, 2H), 7.81 (s, 1H),7.57-7.68 (m, 3H), 7.42 (s, 1H), 7.09-7.13 (m, 3H), 6.86-6.91 (m, 2H),4.59 (s, 2H), 4.45 (s, 2H), 3.86-3.89 (m, 1H), 3.50-3.56 (m, 1H),2.23-2.32 (m, 2H) and 1.72-1.82 (m, 2H) 222

16 28 603.10 (M − H)⁺, 99.06% δ 11.22 (br s, 1H), 8.59-8.63, (m, 2H),7.75-7.81 (m, 2H), 7.64 (t, J = 7.6 Hz, 1H), 7.41- 7.44 (m, 1H), 7.24(s, 1H), 7.00-7.07 (m, 1H), 6.77-6.80 (m, 1H), 4.85-4.89 (m, 1H),4.65-4.71 (m, 2H), 3.31 (s, 1H), 2.92-2.98 (m, 1H), 2.07-2.17 (m, 2H)and 1.84-1.91 (m, 2H) 223

16 34 603.10 (M − H)⁺, 98.00% δ 11 24 (br s, 1H), 8.59-8.62 (m, 2H),8.07-8.11 (m, 1H), 7.99- 8.03 (m, 1H), 7.74 (t, J = 8.0 Hz, 1H),7.42-7.45 (m, 1H), 7.22 (s, 1H), 7.00-7.07 (m, 1H), 6.77- 6.80 (m, 1H),4.65-4.77 (m, 3H), 3.32-3.37 (m, 1H), 2.93-2.99 (m, 1H), 2.12-2.20 (m,2H) and 1.84-1.92 (m, 2H) 224

16 26 544.34 (M + H)⁺, 97.34% δ 10.60 (br s, 1H), 8.61-8.62 (m, 2H),7.99-8.02 (m, 1H), 7.71- 7.33 (m, 1H), 7.65-7.68 (m, 1H), 7.43-7.46 (m,1H), 7.32-7.34 (m, 1H), 7.17 (s, 1H), 7.00-7.07 (m, 1H), 6.76-6.79 (m,1H), 4.61-4.70 (m, 2H), 3.32-3.33 (m, 1H), 2.93-2.99 (m, 1H), 2.07-2.21(m, 2H) and 1.85-1.92 (m, 2H) 225

2 19 613.18 (M + H)⁺, 96.25% δ 8.87 (s, 1H), 8.51-8.53 (m, 1H),8.46-8.47 (m, 1H), 7.59 (d, J = 6.4 Hz, 1H), 7.44-7.49 (m, 2H),7.36-7.39 (m, 1H), 7.23-7.30 (m, 2H), 7.19 (s, 1H), 6.70-6.75 (m, 1H),6.54-6.56 (m, 1H), 4.47-4.59 (m, 4H), 3.81-3.86 (m, 1H), 3.48-3.54 (m,1H), 2.32-2.36 (m, 2H), 2.00 (s, 3H) and 1.71-1.80 (m, 2H) 226

1 10 595.38 (M + H)⁺, 93.90% δ 8.79 (s, 1H), 8.51-8.52 (m, 1H),8.46-8.47 (m, 1H), 7.59 (d, J = 6.4 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H),7.44 (s, 1H), 7.35-7.38 (m, 1H), 7.29-7.31 (m, 1H), 7.18 (s, 1H),7.05-7.09 (m, 2H), 6.82-6.85 (m, 2H), 4.57-4.58 (m, 2H), 4.42-4.48 (m,2H), 3.82-3.85 (m, 1H), 3.50-3.55 (m, 1H), 2.18-2.22 (m, 2H), 2.00 (s,3H) and 1.73- 1.78 (m, 2H) 227

16 38 599.17 (M + H)⁺, 96.76% δ 11.24 (br s, 1H), 8.47-8.53 (m, 2H),7.61 (d, J = 8.0 Hz, 1H), 7.51 (d, J =6.8 Hz, 1H), 7.44 (s, 1H), 7.36(t, J = 8.0 Hz, 1H), 7.30-7.32 (m, 1H), 7.18 (s, 1H), 6.99-7.06 (m, 1H),6.76-6.79 (m, 1H), 4.81-4.84 (m, 1H), 4.61-4.68 (m, 2H), 3.29-3.32 (m,1H), 2.91-2.97 (m, 1H), 2.07-2.20 (m, 2H) and 1.82- 1.91 (m, 2H)

General Procedure for the Preparation of Compounds 15.3 (a-b):

A solution of compound 15.1 (a-b) (2.5 g) in di-ethyl ether was cooledto −78° C. followed by addition of LiHMDS (1.10 eq). The resultingreaction mixture was stirred at −78° C. for 45 min followed by dropwiseaddition of diethyl oxalate 15.2 (1.20 eq) in about 30 min. The reactionmixture was then left to stir at room temperature for 16 h. Aftercompletion of the reaction (TLC and MS monitoring), the solution wasthen cooled 0° C. and the resulting precipitate was filtered to get thedesired product 15.3 (a-b) as an off-white solid, which was carriedforward to the next step without purification.

4-Ethoxy-1-(4-methylpyridin-3-yl)-3,4-dioxobut-1-en-1-olate Lithium Salt(15.3-a)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.44 (s, 1H), 8.38-8.39 (m, 1H), 7.21-7.22(m, 1H), 5.93 (s, 1H), 4.10 (q, J=7.16 Hz, 2H), 2.36 (s, 3H) and 1.20(t, J=7.6 Hz, 3H). MS: 236.0 (M+H)⁺. Yield: quantitative.

4-Ethoxy-3,4-dioxo-1-(pyridazin-4-yl)but-1-en-1-olate Lithium Salt(15.3-b)

¹H-NMR (400 MHz, DMSO-d₆): δ 9.48-9.56 (m, 2H), 9.20-9.21 (m, 1H), 6.46(s, 1H), 4.10 (q, J=7.20 Hz, 2H) and 1.21 (t, J=7.6 Hz, 3H). MS: 223.04(M+H)⁺. Yield: 76%.

General Procedure for the Preparation of Compounds 15.5 (a-b):

To an ice-cold solution of compound 15.3 (a-b) (2.50-3.0 g, 1.0 eq) inIPA was added (3-fluoro-4-(trifluoromethyl)phenyl)hydrazinehydrochloride 15.4 (1.10 eq) and TFA (2.0 eq). The resulting reactionmixture was warmed to room temperature and then stirred at 90° C. for4-5 h. After completion of the reaction (TLC monitoring), the solventwas evaporated and the residue was diluted with water and extracted withethyl acetate (3 times). The combined organics were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated. Thecrude was purified over silica gel (100-200 M, 10-15% EtOAc-hexane) toget the desired product 15.5 (a-b).

Ethyl1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(4-methylpyridin-3-yl)-1H-pyrazole-3-carboxylate(15.5-a)

¹H-NMR (400 MHz, CDCl₃): δ 8.60-8.66 (m, 2H), 7.53-7.55 (m, 1H),7.46-7.47 (m, 1H), 7.21-7.28 (m, 1H), 7.08 (s, 1H), 6.99-7.05 (m, 1H),4.45 (q, J=7.2 Hz, 2H), 2.15 (s, 3H) and 1.42 (t, J=7.6 Hz, 3H). MS:394.33 (M+H)⁺. Yield: 22%.

Ethyl1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(pyridazin-4-yl)-1H-pyrazole-3-carboxylate(15.5-b)

¹H-NMR (400 MHz, CDCl₃): δ 7.61-7.71 (m, 2H), 7.41-7.55 (m, 4H), 7.11(s, 1H), 4.46 (q, J=7.16 Hz, 2H) and 1.42 (t, J=7.24 Hz, 3H). MS: 381.25(M+H)⁺. Yield: 27%.

General Procedure for the Preparation of Compounds 15.6(a-b):

To an ice-cold solution of compound 15.5 (a-b), (1.0-1.2 g) (1.0 eq) inEtOH was added dropwise an aqueous solution of sodium hydroxide (3.0eq). The resulting solution was stirred at room temperature for 2-3 h.After completion of the reaction (TLC monitoring), the solvent wasevaporated, added H₂O to the residue followed by extraction with EtOAc(2×100 mL). The organic layer was discarded and the pH of the aqueouslayer was adjusted to ˜4 by adding 1N HCl. The resulting precipitate wasfiltered and dried under vacuum to get the desired product 15.6 (a-b) asa white solid.

1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(4-methylpyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (15.6-a)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.20 (br s, 1H), 8.50 (d, J=4.12 Hz, 1H),8.39 (s, 1H), 7.82 (t, J=7.88 Hz, 1H), 7.51-7.53 (m, 1H), 7.35-7.37 (m,1H), 7.24-7.26 (m, 1H), 7.17 (s, 1H) and 2.08 (s, 3H). LCMS: 366.22(M+H)⁺, 99.72%. Yield: 60%.

1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(pyridazin-4-yl)-1H-pyrazole-3-carboxylicAcid (15.6-b)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.20 (br s, 1H), 9.24-9.27 (m, 2H),7.89-7.90 (m, 1H), 7.75-7.77 (m, 1H), 7.53-7.54 (m, 1H) and 7.40-7.46(m, 2H). LCMS: 353.19 (M+H)+, 93.39%. Yield: 70%.

General Procedure for the Preparation of Final Compounds (15.7-a and15.7-b):

The final compounds were prepared following the general method N. To anice-cold solution of carboxylic acids 74 (a-b), (125 mg, 1.0 eq), in DMF(2.0 mL) was added DIPEA (3.0 eq) and HATU (1.50 eq). The resultingmixture was stirred under nitrogen atmosphere at 0° C. for 15 minfollowed by addition of6,7-difluoro-1-(piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-oneIntermediate 16 (1.20 eq). The reaction mixture was then stirred at roomtemperature for 16 h. After the completion of the reaction (TLCmonitoring), the solution was diluted with ice-cold water (30 mL)followed by extraction with EtOAc (3×50 mL). The combined organics werewashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude residue was purified viaprep-HPLC.

6,7-difluoro-1-(1-(1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(4-methylpyridin-3-yl)-1H-pyrazole-3-carbonyl)piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one(15.7-a)

¹H-NMR (400 MHz, DMSO-d₆): δ 11.25 (br s, 1H), 8.50-8.52 (m, 1H), 8.42(s, 1H), 7.80 (t, J=8.12 Hz, 1H), 7.51-7.53 (m, 1H), 7.37 (d, J=4.92 Hz,1H), 7.22 (d, J=8.92 Hz, 1H), 7.07 (s, 1H), 7.00-7.05 (m, 1H), 6.77-6.80(m, 1H), 4.81-4.84 (m, 1H), 4.64-4.72 (m, 2H), 3.38-3.41 (m, 1H),2.94-3.00 (m, 1H), 2.10-2.22 (m, 5H), and 1.87-1.90 (m, 2H). LCMS:601.17 (M+H)⁺, 99.94%. Yield: 24%.

6,7-difluoro-1-(1-(1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(pyridazin-4-yl)-1H-pyrazole-3-carbonyl)piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one(15.7-b)

¹H-NMR (400 MHz, DMSO-d₆): δ 11.25 (br s, 1H), 9.26-9.29 (m, 2H),7.89-7.93 (m, 1H), 7.75-7.78 (m, 1H), 7.57 (d, J=4.04 Hz, 1H), 7.42-7.44(m, 2H), 7.00-7.06 (m, 1H), 6.78-6.79 (m, 1H), 4.67-4.77 (m, 3H), 3.32(s, 1H), 2.95-3.00 (m, 1H), 2.08-2.15 (m, 2H) and 1.85-1.92 (m, 2H).LCMS: 588.26 (M+H)⁺, 99.30%. Yield: 32%.

General Procedure for the Preparation of 16.6 (a-d):

General Method I:

To an ice-cold solution of tert-butyl 4-aminopiperidine-1-carboxylate16.2 (1.0-2.5 g, 1.0 eq) in DMF was added DIPEA (1.5 eq) and respectivenitro compounds 16.1 (a-d) (1.0 eq). The resulting reaction mixture wasstirred at RT for 2-3 h. After completion of the reaction (TLCmonitoring), the reaction mass was diluted with ice-cold water andextracted with EtOAc (3 times). The combined organics were washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated. The crudewas purified over silica gel (100-200 M, 10-15% EtOAc-hexane) to get thedesired product 16.3 (a-d).

tert-Butyl 4-((4-cyano-2-nitrophenyl)amino)piperidine-1-carboxylate(16.3-a)

¹H-NMR (400 MHz, CDCl₃): δ 8.42 (d, J=6.8 Hz, 1H), 7.58 (dd, J=2.0 & 8.8Hz, 1H), 6.92 (d, J=8.8 Hz, 1H), 4.04-4.06 (m, 2H), 3.67-3.74 (m, 1H),3.01-3.06 (m, 2H), 2.04-2.07 (m, 2H), 1.59-1.63 (m, 3H) and 1.47 (s,9H). LCMS: 345.53 (M−H)⁺, 92.45%. Yield: 57%.

tert-Butyl 4-((2-cyano-6-nitrophenyl)amino)piperidine-1-carboxylate(16.3-b)

¹H-NMR (400 MHz, CDCl₃): δ 8.37-8.40 (m, 1H), 7.73-7.75 (m, 1H),6.72-6.76 (m, 1H), 4.47-4.54 (m, 1H), 4.04-4.06 (m, 2H), 3.01-3.03 (m,2H), 2.12-2.15 (m, 2H), 1.50-1.56 (m, 3H) and 1.44 (s, 9H). LCMS: 345.28(M−H)⁺, 95.79%. Yield: 77%.

tert-Butyl4-((2-cyano-3-fluoro-6-nitrophenyl)amino)piperidine-1-carboxylate(16.3-c)

¹H-NMR (400 MHz, CDCl₃): δ 8.81-8.83 (m, 1H), 8.44-8.48 (m, 1H),6.49-6.54 (m, 1H), 4.53-4.60 (m, 1H), 4.07-4.10 (m, 2H), 3.00-3.06 (m,2H), 2.14-2.17 (m, 2H), 1.62-1.67 (m, 2H) and 1.40 (s, 9H). LCMS: 363.32(M−H)⁺, 97.61%. Yield: 59%.

tert-Butyl4-((4-cyano-5-fluoro-2-nitrophenyl)amino)piperidine-1-carboxylate(16.3-d)

¹H-NMR (400 MHz, CDCl₃): δ 8.51-8.56 (m, 2H), 8.60-8.63 (m, 1H),4.04-4.07 (m, 2H), 3.57-3.61 (m, 1H), 3.01-3.07 (m, 2H), 2.03-2.06 (m,2H), 1.56-1.60 (m, 2H) and 1.47 (s, 9H). MS: 363.37 (M−H)⁺. Yield: 77%.

General Procedure for the Preparation of 16.4 (a-d):

General Method J:

To a solution of compound 16.3 (a-d) (1.0-2.5 g, 1.0 eq) in EtOAc wereadded Pd—C (w/w, 10 mol %) and the resulting solution was stirred underhydrogen atmosphere (1 atm) at ambient temperature for 16 h. Thereaction mixture was filtered through diatomaceous earth (Celite) bedand the filtrate was concentrated under reduced pressure to get thedesired product 16.4 (a-d).

tert-Butyl 4-((2-amino-4-cyanophenyl)amino)piperidine-1-carboxylate(16.4-a)

¹H-NMR (400 MHz, DMSO-d₆): δ 6.89 (d, J=6.8 Hz, 1H), 6.77 (s, 1H),6.54-6.56 (m, 1H), 5.11-5.12 (m, 1H), 4.98 (br s, 2H), 3.89-3.91 (m,2H), 3.52 (br s, 1H), 2.89 (s, 2H), 1.88-1.90 (m, 2H) and 1.17-1.29 (m,11H). MS: 315.18 (M−H)⁺. Yield: 78%.

tert-Butyl 4-((2-amino-6-cyanophenyl)amino)piperidine-1-carboxylate(16.4-b)

¹H-NMR (400 MHz, DMSO-d₆): δ 6.95-6.96 (m, 1H), 6.88-6.91 (m, 2H),4.11-4.12 (m, 2H), 3.48-3.49 (m, 1H), 3.34-3.37 (m, 1H), 2.73-2.79 (m,2H), 1.89-1.92 (m, 2H), 1.59-1.61 (m, 2H) and 1.45-1.49 (m, 11H). MS:315.55 (M−H)⁺. Yield: 40%.

tert-Butyl4-((6-amino-2-cyano-3-fluorophenyl)amino)piperidine-1-carboxylate(16.4-c)

¹H-NMR (400 MHz, DMSO-d₆): δ 6.81-6.84 (m, 1H), 6.54-6.58 (m, 1H),4.09-4.14 (m, 2H), 3.78-3.82 (m, 1H), 3.66-3.68 (m, 1H), 3.44-3.48 (m,2H), 2.80-2.85 (m, 2H), 1.95-1.98 (m, 2H) and 1.43-1.48 (m, 11H). LCMS:333.56 (M−H)⁺, 82.07%. Yield: 88%.

tert-Butyl4-((2-amino-4-cyano-5-fluorophenyl)amino)piperidine-1-carboxylate(16.4-d)

¹H-NMR (400 MHz, CDCl₃): δ 6.92-6.94 (m, 1H), 6.30-6.36 (m, 1H),4.39-4.41 (br s, 1H), 4.06-4.10 (m, 2H), 3.38-3.40 (m, 2H), 2.91-2.97(m, 2H), 2.00-2.03 (m, 2H) and 1.48 (s, 12H). MS: 333.56 (M−H)⁺. Yield:62%.

General Procedure for the Preparation of 16.5 (a-d):

General Method L:

To an ice-cold solution of compound 16.4 (a-d) (0.50-1.50 g, 1.0 eq) inTHF was added Et₃N (2.0 eq) and triphosgene (1.5 eq). The resultingreaction mixture was stirred at RT for 4 h. After completion of thereaction (TLC monitoring), the solvent was evaporated and the residuewas diluted with water and extracted with ethyl acetate (3 times). Thecombined organics were washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated. The crude was purified over silica gel(100-200 M, 30-40% EtOAc-hexane) to get the desired product 16.5 (a-d).

Tert-butyl4-(5-cyano-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate(16.5-a)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.08 (br s, 1H), 7.38-7.40 (m, 2H),7.18-7.20 (m, 1H), 4.43-4.46 (m, 1H), 4.32-4.36 (m, 2H), 2.87-2.87 (m,2H), 2.25-2.28 (m, 2H), 1.83-1.85 (m, 2H) and 1.44 (s, 9H). LCMS: 343.41(M+H)⁺, 93.09%. Yield: 90%.

Tert-butyl4-(7-cyano-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate(16.5-b)

LCMS: 341.14 (M−H)⁺, 83.61%. Yield: 75%.

Tert-butyl4-(7-cyano-6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate(16.5-c)

LCMS: 359.32 (M−H)⁺, 83.11%. Yield: 48%.

Tert-butyl4-(5-cyano-6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate(16.5-d)

LCMS: 359.57 (M−H)⁺, 81.30%. Yield: 82%.

General Procedure for the Preparation of 16.6 (a-d):

General Method M:

An ice-cold solution of compound 16.5 (a-d) (0.5 g-1.0 g, 1.0 eq) indioxane-HCl (˜4N) was stirred at RT for 2 h. After completion of thereaction (TLC monitoring), the reaction mass was dried under reducedpressure. The crude was triturated with diethyl ether to get desiredproduct 16.6 (a-d) as off solid.

2-Oxo-1-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrileHydrochloride (16.6-a): Intermediate 23

¹H-NMR (400 MHz, DMSO-d₆): δ 11.45 (br s, 1H), 9.11 (br s, 2H), 7.64 (d,J=8.0 Hz, 1H), 7.50-7.52 (m, 1H), 7.40-7.41 (m, 1H), 4.56-4.62 (m, 1H),3.34-3.41 (m, 2H), 3.03-3.08 (m, 2H), 2.58-2.64 (m, 2H) and 1.83-1.90(m, 2H). LCMS: 243.16 (M+H)⁺, 98.94%. Yield: 89%.

2-Oxo-3-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-4-carbonitrileHydrochloride (16.6-b): Intermediate 24

¹H-NMR (400 MHz, DMSO-d₆): δ 11.50 (br s, 1H), 9.13 (br s, 1H), 8.62 (brs, 1H), 7.40-7.42 (m, 1H), 7.32-7.36 (m, 1H), 7.28-7.30 (m, 1H),4.72-4.78 (m, 1H), 3.35-3.48 (m, 2H), 2.86-2.95 (m, 2H), 2.67-2.72 (m,2H) and 2.06-2.09 (m, 2H). LCMS: 241.05 (M−H)⁺, 89.68%. Yield: 95%.

5-Fluoro-2-oxo-3-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-4-carbonitrileHydrochloride (16.6-c): Intermediate 25

¹H-NMR (400 MHz, DMSO-d₆): δ 11.58 (br s, 1H), 9.35 (br s, 1H), 8.76 (brs, 1H), 7.20-7.25 (m, 1H), 7.06-7.11 (m, 1H), 4.65-4.71 (m, 1H),3.56-3.63 (m, 2H), 2.85-2.90 (m, 2H), 2.67-2.73 (m, 2H) and 2.08-2.11(m, 2H). LCMS: 260.96 (M+H)⁺, 95.41%. Yield: 28%.

6-Fluoro-2-oxo-1-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrileHydrochloride (16.6-d): Intermediate 26

¹H-NMR (400 MHz, DMSO-d₆): δ 10.51 (br s, 1H), 9.13-9.24 (m, 2H), 7.76(d, J=8.8 Hz, 1H), 7.40 (d, J=5.2 Hz, 1H), 4.55-4.61 (m, 1H), 3.31-3.35(m, 2H), 3.04-3.07 (m, 2H), 2.60-2.66 (m, 2H) and 1.84-1.87 (m, 2H).LCMS: 259.2 (M−H)⁺, 97.74%. Yield: 91%.

Preparation of tert-butyl3-((2,3-difluoro-6-nitrophenyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate(17.3)

This compound was prepared following the general method I. ¹H-NMR (400MHz, CDCl₃): δ 8.61 (d, J=6.0 Hz, 1H), 8.01-8.04 (m, 1H), 6.45-6.51 (m,1H), 4.21-4.31 (m, 3H), 2.29-2.35 (m, 2H), 2.07-2.09 (m, 2H), 1.94-1.96(m, 2H), 1.68-1.73 (m, 2H) and 1.47 (s, 9H). LCMS: 384.36 (M+H)+,99.35%. Yield: 78%.

Preparation of tert-butyl3-((6-amino-2,3-difluorophenyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate(17.4)

This compound was prepared following the general method J. ¹H-NMR (400MHz, DMSO-d₆): δ 6.57-6.60 (m, 1H), 6.39-6.41 (m, 1H), 4.70 (br s, 2H),4.17-4.19 (m, 1H), 4.01-4.08 (m, 2H), 3.64 (br s, 1H), 1.98-2.06 (m,4H), 1.84-1.86 (m, 2H), 1.61-1.64 (m, 2H) and 1.38 (s, 9H). MS: 354.13(M+H)⁺. Yield: 95%.

Preparation of tert-butyl3-(6,7-difluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate(17.5)

This compound was prepared following the general method L. ¹H-NMR (400MHz, CDCl₃): δ 10.03 (br s, 1H), 6.85-6.97 (m, 1H), 6.74-6.75 (m, 1H),4.52-4.59 (m, 1H), 4.34-4.46 (m, 2H), 2.52-2.54 (m, 2H), 2.06-2.10 (m,2H), 1.80-1.89 (m, 4H) and 1.52 (s, 9H). LCMS: 378.13 (M−H)⁺, 96.51%.Yield: 85%.

Preparation of1-(8-azabicyclo[3.2.1]octan-3-yl)-6,7-difluoro-1,3-dihydro-2H-benzo[d]imidazol-2-oneHydrochloride (17.6): Intermediate 27

This compound was prepared following the general method M. ¹H-NMR (400MHz, DMSO-d₆): δ 11.34 (br s, 1H), 9.02 (br s, 1H), 8.87 (br s, 1H),7.03-7.10 (m, 1H), 6.80-6.81 (m, 1H), 4.89-4.93 (m, 1H), 4.08-4.10 (m,2H), 2.49-2.52 (m, 2H), 2.08-2.09 (m, 2H) and 1.90-1.97 (m, 4H). LCMS:278.06 (M−H)⁺, 99.73%. Yield: 94%.

TABLE 6.5 Tabulated data of the final compounds including the individualyields Amine intermediate Yield ¹H-NMR data (DMSO-d₆, 400 No. Structureused (%) LCMS MHz), unless otherwise specified 228

23 38 573.86 (M − H)⁺, 98.22% δ 11.31 (br s, 1H), 8.60-8.62 (m, 2H),7.85 (t, J = 8.40 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.64-7.67 (m, 1H),7.44-7.47 (m, 3H), 7.37 (s, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.17 (s, 1H),4.70-4.78 (m, 2H), 4.54- 4.57 (m, 1H), 3.28-3.32 (m, 1H), 2.92-2.98 (m,1H), 2.25-2.28 (m, 2H) and 1.79-1.83 (m, 2H) 229

23 35 541.85 (M − H)⁺, 98.34% δ 11.36 (br s, 1H), 8.60-8.61 (m, 2H),7.67-7.69 (m, 1H), 7.41-7.53 (m, 5H), 7.37 (s, 1H), 7.15 (s, 1H),4.69-4.77 (m, 2H), 4.53-4.56 (m, 1H), 3.29-3.32 (m, 1H), 2.92-2.97 (m,1H), 2.25-2.29 (m, 2H) and 1.79-1.87 (m, 2H) 230

Commercial 23 569.82 (M + H)⁺, 98.81% δ 10.36 (br s, 1H), 8.61-8.63 (m,2H), 7.84 (t, J = 8.0 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.66-7.69 (m,1H), 7.44-7.48 (m, 1H), 7.30- 7.34 (m, 2H), 7.17 (s, 1H), 7.10- 7.15 (m,1H), 6.90-6.93 (m, 1H), 4.58-4.68 (m, 2H), 3.50-3.56 (m, 1H), 3.11-3.18(m, 1H) and 2.02- 2.18 (m, 4H) 231

Commercial 21 537.86 (M + H)⁺, 97.64% δ 10.36 (br s, 1H), 8.60-8.61 (m,2H), 7.67 (d, J = 8.0 Hz, 1H), 7.49-7.53 (m, 2H), 7.42-7.45 (m, 1H),7.29-7.31 (m, 1H), 7.14 (s, 1H), 7.11-7.13 (m, 1H), 6.89- 6.93 (m, 1H),4.57-4.67 (m, 2H), 3.48-3.52 (m, 1H), 3.10-3.17 (m, 1H) and 2.01-2.13(m, 4H) 232

24 10 542.41 (M − H)⁺, 97.92% δ 11.25 (br s, 1H), 8.60-8.61 (m, 2H),7.68 (d, J = 7.6 Hz, 1H), 7.51 (t, J = 8.4 Hz, 2H), 7.39-7.45 (m, 2H),7.26 (d, J = 8.0 Hz, 1H), 7.11-7.13 (m, 2H), 4.85-4.85 (m, 2H),4.74-4.77 (m, 1H), 3.78-3.81 (m, 1H), 3.22-3.26 (m, 2H), 2.76- 2.77 (m,1H) and 1.94-1.96 (m, 2H) 233

25 11 560.43 (M − H)⁺, 95.31% δ 11.48 (br s, 1H), 8.61-8.62 (m, 2H),7.70 (d, J = 7.6 Hz, 1H), 7.47-7.55 (m, 2H), 7.44-7.46 (m, 1H),7.23-7.27 (m, 1H), 7.13 (s, 1H), 7.05-7.08 (m, 1H), 4.83- 4.85 (m, 2H),4.73-4.80 (m, 1H), 3.76-3.81 (m, 1H), 3.22-3.26 (m, 2H), 2.80-2.86 (m,1H) and 1.96-1.99 (m, 2H) 234

26 19 592.11 (M − H)⁺, 98.27% δ 11.45 (br s, 1H), 8.60-8.62 (m, 2H),7.85 (t, J = 8.0 Hz, 1H), 7.75 (d, J = 8.00 Hz, 1H), 7.62- 7.67 (m, 2H),7.46-7.49 (m, 1H), 7.33-7.38 (m, 2H), 7.17 (s, 1H), 4.70-4.78 (m, 2H),4.50-4.56 (m, 1H), 3.27-3.33 (m, 1H), 2.89- 2.92 (m, 1H), 2.30-2.35 (m,2H) and 1.78-1.86 (m, 2H) 235

26 48 560.42 (M − H)⁺, 98.73% δ 11.39 (br s, 1H), 8.59-8.60 (m, 2H),7.67 (d, J = 8.0 Hz, 1H), 7.61-7.64 (m, 1H), 7.49 (t, J = 8.4 Hz, 2H),7.41-7.43 (m, 1H), 7.37 (d, J = 5.6 Hz, 1H), 7.14 (s, 1H), 4.69-4.80 (m,2H), 4.49-4.55 (m, 1H), 2.87-2.94 (m, 1H), 2.25-2.36 (m, 3H) and1.78-1.86 (m. 2H) 236

16 28 635.45 (M − H)⁺, 99.95% δ 11.21 (br s, 1H), 8.51-8.54 (m, 2H),8.33 (s, 1H), 8.20 (d, J = 8.40 Hz, 1H), 7.90 (d, J = 8.40 Hz, 1H), 7.59(d, J = 8.0 Hz, 1H), 7.36-7.40 (m, 1H), 7.25 (s, 1H), 6.98-7.05 (m, 1H),6.76-6.79 (m, 1H), 4.62-4.76 (m, 3H), 3.21- 3.25 (m, 1H), 2.92-2.98 (m,1H), 2.07-2.12 (m, 2H) and 1.79-1.91 (m, 2H) 237

16 20 627.09 (M + H)⁺, 99.86% δ 11.25 (br s, 1H), 8.56-8.60 (m, 2H),7.80 (d, J = 8.40 Hz, 2H), 7.71-7.73 (m, 1H), 7.45-7.48 (m, 1H), 7.18(d, J = 8.4 Hz, 1H), 1H), 7.13 (s, 1H), 7.06-7.09 (m, 1H), 7.01-7.03 (m,1H), 6.77- 6.80 (m, 1H), 4.83-4.86 (m, 1H), 4.62-4.70 (m, 2H), 3.33-3.36 (m, 1H), 2.94-2.97 (m, 1H), 2.13-2.17 (m, 2H) and 1.83-1.90 (m, 2H)238

1 13 617.16 (M + H)⁺, 95.05% δ 8.83-8.85 (m, 1H), 8.44-8.47 (m, 1H),7.86 (t, J = 8.4 Hz, 1H), 7.75-7.77 (m, 1H), 7.66- 7.69 (m, 1H), 7.58(d, J = 7.6 Hz, 1H), 7.30-7.32 (m, 1H), 7.16 (s, 1H), 7.08-7.12 (m, 2H),6.84-6.88 (m, 2H), 4.59-4.60 (m, 2H), 4.38-4.44 (m, 2H), 3.88-3.90 (m,1H), 3.51-3.54 (m, 1H), 2.26-2.30 (m, 2H) and 1.78-1.83 (m, 2H) 239

16 8 621.24 (M + H)⁺, 98.56% δ 11.25 (br s, 1H), 8.48-4.49 (m, 1H), 7.88(t, J = 8.0 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.76- 7.77 (m, 1H), 7.58(d, J = 8.0 Hz, 1H), 7.36 (d, J = 7.20 Hz, 1H), 7.21 (s, 1H), 7.02-7.05(m, 1H), 6.77-6.80 (m, 1H), 4.77-4.80 (m, 1H), 4.66-4.70 (m, 2H), 3.33-3.36 (m, 1H), 2.94-2.97 (m, 1H), 2.11-2.17 (m, 2H) and 1.85-1.88 (m, 2H)240

20 9 576.41 (M + H)⁺, 99.91% δ 11.45 (br s, 1H), 8.58-8.59 (m, 2H),7.81-7.84 (m, 2H), 7.73- 7.76 (m, 2H), 7.60-7.64 (m, 1H), 7.43-7.45 (m,2H), 7.10-7.14 (m, 2H), 4.71-4.79 (m, 2H), 4.51- 4.54 (m, 1H), 3.23-3.27(m, 1H), 2.89-2.95 (m, 1H), 2.32-2.35 (m, 2H) and 1.77-1.85 (m, 2H) 241

16 18 587.46 (M + H)⁺, 97.82% δ 11.25 (br s, 1H), 8.58-8.59 (m, 2H),7.82-7.83 (m, 1H), 7.72- 7.75 (m, 2H), 7.59 (t, J = 8.4 Hz, 1H),7.43-7.46 (m, 1H), 7.14 s, 1H), 7.04-7.07 (m, 1H), 6.77- 6.80 (m, 1H),4.78-4.81 (m, 1H), 4.67-4.80 (m, 2H), 3.31-3.34 (m, 1H), 2.92-2.99 (m,1H), 2.11- 2.17 (m, 2H) and 1.84-1.87 (m, 2H) 242

6 16 611.24 (M + H)⁺, 96.86% δ 8.74 (br s, 1H), 8.60-8.61 (m, 2H),7.79-7.80 (m, 1H), 7.58- 7.73 (m, 3H), 7.44-7.47 (m, 1H), 7.10 (s, 1H),6.57 (d, J = 5.6 Hz, 2H), 4.55 (s, 2H), 4.36- 4.39 (m, 2H), 3.79-3.85(m, 1H), 3.47-3.53 (m, 1H), 2.29-2.32 (m, 1H), 2.17-2.20 (m, 1H), 2.10(s, 6H) and 1.70-1.76 (m, 2H) 243

24 12 576.15 (M + H)⁺, 91.27% δ 11.24 (br s, 1H), 8.61-8.62 (m, 2H),7.85 (t, J = 8.4 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.66- 7.69 (m, 1H),7.40-7.46 (m, 2H), 7.28-7.35 (m, 2H), 7.15 (s, 1H), 7.10-7.11 (m, 1H),4.83-4.86 (m, 2H), 4.74-4.77 (m, 1H), 3.32- 3.40 (m, 1H), 3.21-3.27 (m,2H), 2.95-3.00 (m, 1H) and 1.98-2.01 (m, 2H) 244

25 10 592.04 (M − H)⁺, 97.13% δ 11.24 (br s, 1H), 8.60-8.62 (m, 2H),7.85 (t, J = 8.80 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.66- 7.69 (m, 1H),7.44-7.47 (m, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.23- 7.27 (m, 1H), 7.15(s, 1H), 7.05- 7.10 (m, 1H), 4.73-4.87 (m, 3H), 3.15-3.20 (m, 2H),2.81-2.84 (m, 1H) and 1.92-2.02 (m, 3H) 245

16 12 594.16 (M + H)⁺, 95.67% δ 11.25 (br s, 1H), 9.41 (s, 1H),8.84-8.85 (m, 1H), 8.70-8.72 (m, 1H), 8.65 (s, 1H), 8.07-8.10 (m, 2H),7.91-7.93 (m, 1H), 7.72- 7.75 (m, 1H), 7.03-7.08 (m, 1H), 6.79-6.81 (m,1H), 4.69-4.76 (m, 2H), 4.09-4.13 (m, 1H), 3.07- 3.15 (m, 2H), 1.97-2.00(m, 2H) and 1.74-1.82 (m, 2H) 246

1 10 623.08 (M + H)⁺, 90.04% δ 8.79 (br s, 1H), 8.56-8.57 (m, 1H), 8.51(s, 1H), 7.78-7.80 (m, 2H), 7.64-7.66 (m, 1H), 7.40-7.43 (m, 1H),7.07-7.14 (m, 5H), 6.84- 6.86 (m, 2H), 4.53 (s, 2H), 4.41- 4.43 (m, 2H),3.84-3.89 (m, 1H), 3.49-3.55 (m, 1H), 2.14-2.21 (m, 2H) and 1.73-1.77(m, 2H) 247

16 13 619.03 (M − H)⁺, 95.97% δ 11.10 (br s, 1H), 8.55-8.56 (m, 1H),8.13-8.15 (m, 1H), 7.83 (t, J = 8.0 Hz, 1H), 7.56-7.63 (m, 2H), 7.22 (d,J = 8.8 Hz, 1H), 7.12 (s, 1H), 7.01-7.05 (m, 1H), 6.77-6.81 (m, 1H),4.79-4.82 (m, 1H), 4.68-4.71 (m, 2H), 3.37- 3.41 (m, 1H), 2.95-3.01 (m,1H), 2.12-2.21 (m, 2H) and 1.91-1.99 (m, 2H) 248

16 20 544.12 (M + H)⁺, 98.99% δ 11.25 (br s, 1H), 8.58-8.59 (m, 2H),8.11-8.13 (m, 1H), 7.75- 7.80 (m, 1H), 7.60-7.67 (m, 2H), 7.40-7.43 (m,1H), 7.15 (s, 1H), 6.96-7.03 (m, 1H), 6.75-6.78 (m, 1H), 4.82-4.85 (m,1H), 4.68- 4.70 (m, 2H), 3.33 (s, 1H), 2.91- 2.98 (m, 1H), 2.13-2.15 (m,2H) and 1.83-1.90 (m, 2H) 249

6 10 566.08 (M − H)⁺, 99.21% δ 8.76 (br s, 1H), 8.56-8.59 (m, 2H),8.05-8.07 (m, 1H), 7.70- 7.74 (m, 1H), 7.59-7.66 (m, 2H), 7.40-7.43 (m,1H), 7.10 (s, 1H), 6.57 (d, J = 6.4 Hz, 2H), 4.55 (s, 2H), 4.38-4.40 (m,2H), 3.79- 3.86 (m, 1H), 3.47-3.53 (m, 1H), 2.27-2.29 (m, 1H), 2.17-2.18(m, 1H), 2.11 (s, 6H) and 1.71-1.79 (m, 2H) 250

27 25 581.12 (M + H)⁺, 95.59% δ 11.20 (br s, 1H), 8.58-8.60 (m, 2H),7.69-7.70 (m, 1H), 7.52- 7.55 (m, 2H), 7.42-7.45 (m, 1H), 7.22 (s, 1H),7.01-7.08 (m, 1H), 6.77-6.79 (m, 1H), 5.34 (m, 1H), 4.86 (m, 1H),4.36-4.38 (m, 1H), 2.49 (m, 1H), 2.00-2.11 (m, 2H) and 1.84-1.92 (m, 5H)

General Procedure for the Preparation of Compounds 18.2 (a-c):

A solution of compound 18.1 (a-c) (1 eq) in di-ethyl ether was cooled to−78° C. followed by addition of LiHMDS-THF (1M solution, 1.10 eq). Theresulting reaction mixture was stirred at −78° C. for 45 min followed bydropwise addition of diethyl oxalate (1.20 eq) in about 30 min. Thereaction mixture was then left to stir at room temperature for 16 h.After completion of the reaction (TLC and MS monitoring), the solutionwas then cooled 0° C. and the resulting precipitate was filtered to getthe desired product as an off-white solid 18.2 (a-c), which was carriedforward to the next step without purification.

4-Ethoxy-3,4-dioxo-1-(pyridin-4-yl)but-1-en-1-olate Lithium Salt (18.2a)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.93 (s, 1H), 8.62 (m, 1H), 8.10 (m, 1H),7.40 (m, 1H), 6.38 (m, 1H), 4.11 (q, J=7.20 Hz, 2H) and 1.22 (t, J=7.2Hz, 3H). MS: 221.96 (M+H)⁺. Yield: 90%.

4-Ethoxy-3,4-dioxo-1-(pyridin-3-yl)but-1-en-1-olate Lithium Salt (18.2b)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.97 (s, 1H), 8.63 (d, J=4.0 Hz, 1H), 8.14(m, 1H), 7.43 (m, 1H), 6.41 (m, 1H), 4.13 (q, J=7.20 Hz, 2H) and 1.23(t, J=7.2 Hz, 3H). MS: 221.92 (M+H)⁺. Yield: 76%.

4-Ethoxy-3,4-dioxo-1-(pyridin-2-yl)but-1-en-1-olate Lithium Salt (18.2c)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.60 (d, J=4.4 Hz, 1H), 7.98 (m, 1H), 7.87(m, 1H), 7.45 (m, 1H), 6.48 (s, 1H), 4.15 (q, J=7.20 Hz, 2H) and 1.19(t, J=6.8 Hz, 3H). MS: 221.97 (M+H)⁺. Yield: 96%.

General Procedure for the Preparation of Compounds 18.3 (a-c):

To an ice-cold solution of compound 18.2 (a-c), (1.0 eq) in IPA wasadded 3,4,5-trifluorophenyl hydrazine HCl (1.10 eq) and TFA (2.0 eq).The resulting reaction mixture was warmed to room temperature and thenstirred at 90° C. for 4-5 h. After completion of the reaction (TLCmonitoring), the solvent was evaporated and the residue was diluted withwater and extracted with ethyl acetate (3 times). The combined organicswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated. The crude was purified over silica gel (100-200 M,10-15% EtOAc-hexane) to get the desired products 18.3 (a-c).

Ethyl5-(pyridin-4-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carboxylate(18.3a)

¹H-NMR (400 MHz, CDCl₃): δ 8.70 (m, 1H), 8.65 (s, 1H), 7.62 (d, J=8.0Hz, 1H), 7.42 (m, 1H), 7.15 (s, 1H), 7.03 (m, 2H), 4.49 (q, J=7.2 Hz,2H) and 1.45 (t, J=7.2 Hz, 3H). MS: 348.09 (M+H)⁺. Yield: 28%.

Ethyl5-(pyridin-3-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carboxylate(18.3b)

¹H-NMR (400 MHz, CDCl₃): δ 8.67 (m, 1H), 8.60 (s, 1H), 7.59 (d, J=8.0Hz, 1H), 7.41 (m, 1H), 7.12 (s, 1H), 7.00 (m, 2H), 4.47 (q, J=7.2 Hz,2H) and 1.43 (t, J=7.2 Hz, 3H). MS: 348.15 (M+H)⁺. Yield: 22%.

Ethyl5-(pyridin-2-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carboxylate(18.3c)

¹H-NMR (400 MHz, CDCl₃): δ 8.53 (m, 1H), 7.75 (m, 1H), 7.45 (d, J=8.0Hz, 1H), 7.30 (m, 1H), 7.23 (s, 1H), 7.03 (m, 2H), 4.39 (q, J=6.8 Hz,2H) and 1.41 (t, J=7.2 Hz, 3H). MS: 347.88 (M+H)⁺. Yield: 23%.

General Procedure for the Preparation of Compounds 18.4 (a-c):

To an ice-cold solution of compound 18.3 (a-c) (1.0 eq) in EtOH wasadded dropwise an aqueous solution of sodium hydroxide (3.0 eq). Theresulting solution was stirred at room temperature for 2-3 h. Aftercompletion of the reaction (TLC monitoring), the solvent was evaporated,added H₂O to the residue followed by extraction with EtOAc (2×100 mL).The organic layer was discarded and the pH of the aqueous layer wasadjusted to ˜4 by adding 1N HCl. The resulting precipitate was filteredand dried under vacuum to get the desired products 18.4 (a-c) as a whitesolid.

5-(pyridin-4-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carboxylic Acid(18.4a)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.40 (br s, 1H), 8.62 (m, 2H), 7.68 (d,J=8.0 Hz, 1H), 7.56 (m, 2H), 7.45 (m, 1H) and 7.22 (s, 1H). LCMS: 320.17(M+H)⁺, 96.12%. Yield: 65%.

5-(pyridin-3-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carboxylic Acid(18.4b)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.12 (br s, 1H), 8.58 (s, 2H), 7.64 (d,J=8.4 Hz, 1H), 7.50 (m, 2H), 7.40 (m, 1H) and 7.24 (s, 1H). LCMS: 320.14(M+H)⁺, 94.25%. Yield: 61%.

5-(pyridin-2-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carboxylic Acid(18.4c)

¹H-NMR (400 MHz, DMSO-d₆): 6.8.45 (d, J=5.4 Hz, 1H), 7.87 (m, 1H), 7.72(d, J=8.0 Hz, 1H), 7.35 (m, 3H) and 7.25 (s, 1H). LCMS: 320.12 (M+H)⁺,98.46%. Yield: 55%.

General Procedure for the Preparation of Final Compounds 5 (18.a-h):

To an ice-cold solution of carboxylic acids 18.4 (a-c) (1.0 eq), in DMF(2.0 mL) was added DIPEA (3.0 eq) and HATU (1.50 eq). The resultingmixture was stirred under nitrogen atmosphere at 0° C. for 15 minfollowed by addition of respective amines (1.20 eq). The reactionmixture was then stirred at room temperature for 16 h. After thecompletion of the reaction (TLC monitoring), the solution was dilutedwith ice-cold water (30 mL) followed by extraction with EtOAc (3×50 mL).The combined organics were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The cruderesidue was purified via prep-HPLC.

Individual yields and the analytical data of the final compoundssynthesized via scheme 18 are set forth in Table 6.6.

TABLE 6.6 Tabulated data of the final compounds including the individualyields obtained via scheme 18. Compound Yield NMR data (DMSO-d₆, 400MHz), No. Structure (%) LCMS unless otherwise specified 251

23 555.11 (M + H)⁺, 99.32% δ 11.9 (br s, 1H), 8.59 (d, J = 6.0 Hz, 2H),7.54 (t, J = 7.6 Hz, 2H), 7.31 (d, J = 5.6 Hz, 2H), 7.23 (s, 1H),7.00-7.07 (m, 1H), 6.77-6.80 (m, 1H), 4.78-4.81 (m, 1H), 4.67-4.70 (m,2H), 3.29 (s, 1H), 2.92-2.98 (m, 1H), 2.07-2.13 (m, 2H) and 1.84-1.87(m, 2H) 252

15 555.09 (M + H)⁺, 99.89% δ 11.25 (br s, 1H), 8.47 (s, 1H), 7.91 (s,1H), 7.71 (s, 1H), 7.48 (s, 2H), 7.38 (s, 1H), 7.25 (s, 1H), 7.04-7.09(m, 1H), 6.79 (s, 1H), 4.81-4.83 (m, 1H), 4.67- 4.74 (m, 2H), 3.17 (s,1H), 2.94-2.98 (m, 1H), 2.14-2.16 (m, 2H) and 1.83- 1.87 (m, 2H) 253

20 551.13 (M + H)⁺, 99.86% δ 8.80 (s, 1H), 8.59-8.60 (m, 2H), 7.66 (d, J= 7.6 Hz, 1H), 7.41-7.48 (m, 3H), 7.08-7.15 (m, 3H), 6.84-6.87 (m, 2H),4.59 (s, 2H), 4.41-4.49 (m, 2H), 3.83- 3.89 (m, 1H), 3.50-3.56 (m, 1H),2.20- 2.28 (m, 2H) and 1.74-1.83 (m, 2H) 254

19 567.12 (M − H)⁺, 98.45% δ 8.89 (s, 1H), 8.62 (s, 2H), 7.70-7.72 (m,1H), 7.45-7.50 (m, 3H), 7.28-7.31 (m, 1H), 7.15 (s, 1H), 6.74-6.79 (m,1H), 6.57-6.59 (m, 1H), 4.59 (s, 2H), 4.47-4.49 (m, 2H), 3.82-3.85 (m,1H), 3.49-3.53 (m, 1H), 2.33-2.36 (m, 2H) and 1.72-1.76 (m, 2H) 255

23 565.34 (M + H)⁺, 97.49% δ 8.78 (s, 1H), 8.59-8.60 (m, 2H), 7.66 (d, J= 7.6 Hz, 1H), 7.41-7.48 (m, 3H), 7.12 (s, 1H), 7.01-7.05 (m, 1H), 6.68-6.74 (m, 2H), 4.57 (s, 2H), 4.40-4.43 (m, 2H), 3.81-3.84 (m, 1H),3.49-3.51 (m, 1H), 2.23-2.26 (m, 2H), 2.14 (s, 3H) and 1.72-1.76 (m, 2H)256

9.8 520.10 (M + H)⁺, 99.67% δ 11.55 (br s, 1H), 8.60 (s, 2H), 7.89 (d, J= 4.4 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.50(d, J = 7.6 Hz, 2H), 7.41-7.45 (m, 1H), 7.15 (s, 1H), 6.97-7.01 (m, 1H),4.70-4.79 (m, 2H), 4.49-4.55 (m, 1H), 2.90-2.96 (m, 1H), 2.22-2.26 (m,3H) and 1.80-1.84 (m, 2H) 257

15 569.31 (M + H)⁺, 99.50% δ 8.65 (s, 1H), 8.59-8.60 (m, 2H), 7.62 (d, J= 8.0 Hz, 1H), 7.43-7.48 (m, 4H), 7.27-7.30 (m, 1H), 7.07-7.10 (m, 1H),7.04 (s, 1H), 4.53-4.57 (m, 2H), 4.22- 4.26 (m, 1H), 4.10-4.14 (m, 1H),3.87- 3.93 (m, 1H), 3.55-3.61 (m, 1H), 1.87- 1.94 (m, 2H) and 1.37-1.42(m, 2H)

Preparation of 4-ethoxy-3,4-dioxo-1-(pyridin-3-yl)but-1-en-1-olateLithium Salt (19.2-b)

A solution of 3-acetyl pyridine 19.1-b (25 g, 206.37 mmol) in di-ethylether (300 mL) was cooled to −78° C. followed by addition of LiHMDS (1.0M in THF, 250 mL, 227.01 mmol). The resulting reaction mixture wasstirred at −78° C. for 45 min followed by dropwise addition of diethyloxalate (33.8 mL, 247.64 mL) in about 30 min. The reaction mixture wasthen left to stir at room temperature for 16 h. After completion of thereaction (TLC and MS monitoring), the solution was then cooled to 0° C.and the resulting precipitate was filtered to get the desired product asan off-white solid 2 (34 g, 76%), which was carried forward to the nextstep without purification. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.97 (s, 1H),8.63 (d, J=4.0 Hz, 1H), 8.14 (m, 1H), 7.43 (m, 1H), 6.41 (m, 1H), 4.13(q, J=7.20 Hz, 2H) and 1.23 (t, J=7.2 Hz, 3H). MS: 221.92 (M+H)⁺.

Preparation of ethyl1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(19.6)

To an ice-cold solution of4-ethoxy-3,4-dioxo-1-(pyridin-3-yl)but-1-en-1-olate lithium salt 19.2-b(10 g, 45.23 mmol) in IPA (60 mL) was added(3-fluoro-4-(trifluoromethyl)phenyl)hydrazine hydrochloride 10.5 g,54.28 mmol) and TFA (7.25 mL, 90.46 mL). The resulting reaction mixturewas warmed to room temperature and then stirred at 90° C. for 4-5 h.After completion of the reaction (TLC monitoring), the solvent wasevaporated and the residue was diluted with water and extracted withethyl acetate (3 times). The combined organics were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated. Thecrude was purified over silica gel (100-200 M, 10-15% EtOAc-hexane) toget the desired product 19.6 (7.5 g, 41%). ¹H-NMR (400 MHz, CDCl₃): δ8.70 (m, 2H), 7.73 (m, 3H), 7.48 (d, J=7.6 Hz, 1H), 7.46 (d, J=7.6 Hz,1H), 7.13 (s, 1H), 4.47 (q, J=6.8 Hz, 2H) and 1.43 (t, J=7.2 Hz, 3H).MS: 379.88 (M+H)⁺.

Preparation of1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid 19.7

To an ice-cold solution of ethyl1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate19.6 (7.5 g, 19.77 mmol) in EtOH (50 mL) was added dropwise an aqueoussolution of sodium hydroxide (1.6 g in 5 mL H₂O). The resulting solutionwas stirred at room temperature for 2 h. After completion of thereaction (TLC monitoring), the solvent was evaporated, added H₂O to theresidue followed by extraction with EtOAc (2×100 mL). The organic layerwas discarded and the pH of the aqueous layer was adjusted to ˜4 byadding 1N HCl. The resulting precipitate was filtered and dried undervacuum to get the desired product 19.7 (4.0 g, 58%) as a white solid.¹H-NMR (400 MHz, DMSO-d₆): 6.8.58 (m, 2H), 7.86 (t, J=8.0 Hz, 1H), 7.70(d, J=7.6 Hz, 1H), 7.63 (m, 1H), 7.43 (m, 1H), 7.33 (d, J=8.4 Hz, 1H)and 7.24 (s, 1H). LCMS: 351.96 (M+H)⁺, 90.40%.

General Procedure for the Preparation of Final Compounds 19.8 (a-f):

To an ice-cold solution of1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicacid 19.7 (1.0 eq), in DMF (2.0 mL) was added DIPEA (3.0 eq) and HATU(1.50 eq). The resulting mixture was stirred under nitrogen atmosphereat 0° C. for 15 min followed by addition of respective amines (1.20 eq).The reaction mixture was then stirred at room temperature for 16 h.After the completion of the reaction (TLC monitoring), the solution wasdiluted with ice-cold water (30 mL) followed by extraction with EtOAc(3×50 mL). The combined organics were washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude residue was purified via prep-HPLC.

Yields and the analytical data of the final compounds synthesized viascheme 19 are set forth in Table 6.7.

TABLE 6.7 Tabulated data of the final compounds including the individualyields obtained via scheme 19. Compound Yield NMR data (DMSO-d₆, 400MHz), No. Structure (%) LCMS unless otherwise specified 258

20 551.15 (M + H)⁺, 98.86% δ 10.39 (br s, 1H), 8.58-8.61 (m, 2H), 7.83(t, J = 8.4 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.65-7.67 (m, 1H),7.43-7.46 (m, 1H), 7.29-7.32 (m, 2H), 7.19 (d, J = 7.6 Hz, 1H), 7.12 (s,1H), 6.96 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 4.43 (s, 1H),3.96-3.98 (m, 2H), 3.65-3.67 (m, 2H), 2.81-2.86 (m, 2H) and 2.67- 2.68(m, 2H) 259

21 536.12 (M + H)⁺, 96.33% δ 10.48 (br s, 1H), 8.61-8.62 (m, 2H), 7.85(t, J = 8.4 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.64-7.67 (m, 1H), 7.50(d, J = 7.6 Hz, 1H), 7.44-7.46 (m, 1H), 7.32- 7.34 (m, 1H), 7.18-7.22(m, 2H), 7.95 (t, J = 8.4 Hz, 1H), 6.86 (t, J = 8.0 Hz, 1H), 4.22-4.23(m, 2H), 4.00-4.05 (m, 2H) and 1.81-1.83 (m, 4H) 260

12 552.11 (M + H)⁺, 95.74% δ 10.57 (br s, 1H), 8.61-8.62 (m, 2H),7.85-7.89 (m, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.64-7.67 (m, 1H), 7.58 (d,J = 8.0 Hz, 1H), 7.44-7.46 (m, 1H), 7.32-7.35 (m, 1H), 7.17 (s, 1H),6.97-7.01 (m, 1H), 4.70-4.74 (m, 2H), 4.50-4.53 (m, 1H), 3.35-3.37 (m,1H), 2.92-2.95 (m, 1H), 2.23-2.28 (m, 2H) and 1.81-1.86 (m, 2H) 261

19 565.21 (M + H)⁺, 99.87% δ 10.87 (br s, 1H), 8.61-8.62 (m, 2H),7.84-7.88 (m, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.64-7.68 (m, 1H),7.44-7.48 (m, 1H), 7.32-7.34 (m, 2H), 7.18 (s, 1H), 6.98-7.01 (m, 3H),4.37-4.42 (m, 3H), 3.70 (s, 1H), 2.11-2.15 (m, 2H), 1.88- 1.90 (m, 2H)and 1.31-1.33 (d, J = 6.0 Hz, 3H)

Preparation of4-ethoxy-1-(3-fluoro-4-(trifluoromethyl)phenyl)-3,4-dioxobut-1-en-1-olateLithium Salt (20.10)

A solution of 1-(3-fluoro-4-(trifluoromethyl)phenyl)ethan-1-one 20.9 (5g, 24.25 mmol) in diethyl ether (60 mL) was cooled to −78° C. followedby addition of LiHMDS (1.0 M in THF, 27 mL, 26.68 mmol). The resultingreaction mixture was stirred at −78° C. for 45 min followed by dropwiseaddition of diethyl oxalate (4.0 mL, 29.10 mmol) in about 30 min. Thereaction mixture was then left to stir at room temperature for 16 h.After completion of the reaction (TLC and MS monitoring), the solutionwas then cooled 0° C. and the resulting precipitate was filtered to getthe desired product as an off-white solid 20.10 (7.4 g, 99%), which wascarried forward to the next step without purification. ¹H-NMR (400 MHz,DMSO-d₆): δ 7.76 (m, 3H), 6.44 (s, 1H), 4.14 (q, J=7.20 Hz, 2H) and 1.23(t, J=7.2 Hz, 3H). MS: 306.98 (M+H)⁺.

Preparation of ethyl5-(3-fluoro-4-(trifluoromethyl)phenyl)-1-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(20.11)

To an ice-cold solution of4-ethoxy-1-(3-fluoro-4-(trifluoromethyl)phenyl)-3,4-dioxobut-1-en-1-olatelithium salt 20.10 (2.5 g, 8.01 mmol) in IPA (20 mL) was added3-hydrazinylpyridine hydrochloride 1.5 g, 8.01 mmol) and TFA (1.2 mL,16.03 mmol). The resulting reaction mixture was warmed up to roomtemperature and then stirred at 90° C. for 4-5 h. After completion ofthe reaction (TLC monitoring), the solvent was evaporated and theresidue was diluted with water and extracted with ethyl acetate (3times). The combined organics were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated. The crude waspurified over silica gel (100-200 M, 10-15% EtOAc-hexane) to get thedesired product 20.11 (1.0 g, 34%). ¹H-NMR (400 MHz, CDCl₃): δ 8.65 (m,1H), 8.56 (s, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.39(m, 1H), 7.14 (s, 1H), 7.00 (m, 2H), 4.39 (q, J=7.6 Hz, 2H) and 1.42 (t,J=7.2 Hz, 3H). MS: 380.17 (M+H)⁺.

Preparation of5-(3-fluoro-4-(trifluoromethyl)phenyl)-1-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (20.12)

To an ice-cold solution of ethyl5-(3-fluoro-4-(trifluoromethyl)phenyl)-1-(pyridin-3-yl)-1H-pyrazole-3-carboxylate20.11 (1.0 g, 2.63 mmol) in EtOH (30 mL) was added dropwise an aqueoussolution of sodium hydroxide (0.22 g in 3 mL H₂O). The resultingsolution was stirred at room temperature for 2 h. After completion ofthe reaction (TLC monitoring), the solvent was evaporated, added H₂O tothe residue followed by extraction with EtOAc (2×100 mL). The organiclayer was discarded and the pH of the aqueous layer was adjusted to ˜4by adding 1N HCl. The resulting precipitate was filtered and dried undervacuum to get the desired product 20.12 (0.8 g, 86%) as a white solid.¹H-NMR (400 MHz, DMSO-d₆): δ 13.23 (br s, 1H), 8.66 (t, J=4.0 Hz, 1H),8.60 (m, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.77 (t, J=7.6 Hz, 1H), 7.54 (m,2H), 7.34 (s, 1H) and 7.23 (d, J=8.0 Hz, 1H). LCMS: 352.00 (M+H)⁺,95.49%.

Preparation of8-(5-(3-fluoro-4-(trifluoromethyl)phenyl)-1-(pyridin-3-yl)-1H-pyrazole-3-carbonyl)-1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one(Compound 267)

To an ice-cold solution of5-(3-fluoro-4-(trifluoromethyl)phenyl)-1-(pyridin-3-yl)-1H-pyrazole-3-carboxylicacid 20.12 (0.15 g, 0.43 mmol) in DMF (2.0 mL) was added DIPEA (0.22 mL,1.29 mmol) and HATU (0.25 g, 0.65 mmol). The resulting mixture wasstirred under nitrogen atmosphere at 0° C. for 15 min followed byaddition of 1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (0.11g, 0.43 mmol). The reaction mixture was then stirred at room temperaturefor 16 h. After the completion of the reaction (TLC monitoring), thesolution was diluted with ice-cold water (30 mL) followed by extractionwith EtOAc (3×50 mL). The combined organics were washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude residue was purified via prep-HPLC (0.045 g, 18%).¹H-NMR (400 MHz, DMSO-d₆): δ 8.80 (s, 1H), 8.60-8.63 (m, 2H), 7.78-7.83(m, 2H), 7.53-7.56 (m, 1H), 7.50-7.52 (m, 1H), 7.24 (d, J=8.0 Hz, 1H),7.22 (s, 1H), 7.07 (d, J=8.8 Hz, 2H), 6.84-6.87 (m, 2H), 4.58-4.59 (m,2H), 4.42-4.48 (m, 2H), 3.84-3.87 (m, 1H), 3.51-3.56 (m, 1H), 2.19-2.23(m, 2H) and 1.74-1.79 (m, 2H). LCMS: 583.14 (M+H)⁺, 96.73%.

Preparation of 4-ethoxy-3,4-dioxo-1-(pyridin-3-yl)but-1-en-1-olatelithium salt (21.2-b)

Intermediate 21.2-b was prepared as per the procedure mentioned inScheme 19.

Preparation of ethyl1-(3,5-difluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(21.14)

To an ice-cold solution of4-ethoxy-3,4-dioxo-1-(pyridin-3-yl)but-1-en-1-olate lithium salt 21.2-b(1.5 g, 6.78 mmol) in IPA (20 mL) was added(3,5-difluoro-4-(trifluoromethyl)phenyl)hydrazine hydrochloride (1.68 g,6.78 mmol) and TFA (1.0 mL, 13.56 mL). The resulting reaction mixturewas warmed to room temperature and then stirred at 90° C. for 4-5 h.After completion of the reaction (TLC monitoring), the solvent wasevaporated and the residue was diluted with water and extracted withethyl acetate (3 times). The combined organics were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated. Thecrude was purified over silica gel (100-200 M, 10-15% EtOAc-hexane) toget the desired product 21.14 (0.66 g, 25%). ¹H-NMR (400 MHz, CDCl₃): δ8.70 (m, 1H), 8.58 (m, 1H), 7.57 (m, 1H), 7.38 (m, 1H), 7.08 (s, 1H),7.03 (m, 2H), 4.44 (q, J=6.8 Hz, 2H) and 1.41 (t, J=6.8 Hz, 3H). MS:398.16 (M+H)⁺.

Preparation of1-(3,5-difluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (2.15)

To an ice-cold solution of ethyl1-(3,5-difluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate2.14 (0.60 g, 1.65 mmol) in EtOH (20 mL) was added dropwise an aqueoussolution of sodium hydroxide (0.13 g in 3 mL H₂O). The resultingsolution was stirred at room temperature for 2 h. After completion ofthe reaction (TLC monitoring), the solvent was evaporated, added H₂O tothe residue followed by extraction with EtOAc (2×100 mL). The organiclayer was discarded and the pH of the aqueous layer was adjusted to ˜4by adding 1N HCl. The resulting precipitate was filtered and dried undervacuum to get the desired product 2.15 (0.3 g, 51%) as a white solid.¹H-NMR (400 MHz, DMSO-d₆): δ 13.31 (br s, 1H), 8.59 (m, 2H), 7.73 (m,1H), 7.45 (m, 2H), 7.38 (m, 1H) and 7.04 (m, 1H). MS: 368.14 (M−H)⁺.

Preparation of8-(1-(3,5-difluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carbonyl)-1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one(Compound 268)

To an ice-cold solution of1-(3,5-difluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicacid 2.15 (0.10 g, 0.27 mmol) in DMF (2.0 mL) was added DIPEA (0.14 mL,0.81 mmol) and HATU (0.154 g, 0.41 mmol). The resulting mixture wasstirred under nitrogen atmosphere at 0° C. for 15 min followed byaddition of 1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (0.067g, 0.27 mmol). The reaction mixture was then stirred at room temperaturefor 16 h. After the completion of the reaction (TLC monitoring), thesolution was diluted with ice-cold water (30 mL) followed by extractionwith EtOAc (3×50 mL). The combined organics were washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude residue was purified via prep-HPLC (0.035 g, 21%).¹H-NMR (400 MHz, DMSO-d₆+D₂O): δ 8.59-8.60 (m, 1H), 8.54-8.55 (m, 1H),7.75 (d, J=8.0 Hz, 1H) 7.46-7.47 (m, 1H), 7.30-7.32 (m, 2H), 7.05-7.09(m, 3H), 6.84-6.88 (m, 2H), 4.56 (s, 2H), 4.31-4.35 (m, 2H), 3.79-3.81(m, 1H), 3.48-3.51 (m, 1H), 2.15-2.19 (m, 2H) and 1.71-1.75 (m, 2H).LCMS: 601.10 (M+H)⁺, 99.21%.

Preparation of 22.18 (a-b) and 18.1-c:

These intermediates were prepared following the general procedurementioned in Scheme 18.

4-Ethoxy-1-(6-methylpyridin-3-yl)-3,4-dioxobut-1-en-1-olate Lithium Salt(22.18-a)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.85 (s, 1H), 8.03 (d, J=7.2 Hz, 1H), 7.28(d, J=8.0 Hz, 1H), 6.40 (s, 1H), 4.14 (q, J=6.8 Hz, 2H), 2.45 (s, 3H)and 1.25 (t, J=7.2 Hz, 3H). MS: 236.14 (M+H)⁺. Yield: 80%.

4-Ethoxy-1-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)-3,4-dioxobut-1-en-1-olateLithium Salt (22.18-b)

¹H-NMR (400 MHz, DMSO-d₆): δ 7.87 (d, J=7.6 Hz, 1H), 7.70 (d, J=7.2 Hz,1H), 5.91 (s, 1H), 4.17 (q, J=7.6 Hz, 2H), 2.58 (s, 3H) and 1.16 (t,J=7.2 Hz, 3H). MS: 304.12 (M+H)⁺. Yield: 93%.

4-Ethoxy-3,4-dioxo-1-(pyridin-2-yl)but-1-en-1-olate Lithium Salt(18.2-c)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.60 (d, J=4.4 Hz, 1H), 7.98 (m, 1H), 7.87(m, 1H), 7.45 (m, 1H), 6.48 (s, 1H), 4.15 (q, J=7.20 Hz, 2H) and 1.19(t, J=6.8 Hz, 3H). MS: 221.97 (M+H)⁺. Yield: 96%.

Preparation of 22.19 (a-c):

These intermediates were prepared following the general procedurementioned in Scheme 18.

Ethyl1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(6-methylpyridin-3-yl)-1H-pyrazole-3-carboxylate(22.19-a)

¹H-NMR (400 MHz, CDCl₃): δ 8.61 (m, 1H), 7.60 (t, J=8.0 Hz, 1H), 7.53(d, J=8.0 Hz, 1H), 7.32 (m, 2H), 7.13 (m, 2H), 4.44 (q, J=7.2 Hz, 2H),2.68 (s, 3H) and 1.41 (t, J=7.2 Hz, 3H). MS: 394.17 (M+H)⁺. Yield: 57%.

Ethyl1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-3-carboxylate(22.19-b)

¹H-NMR (400 MHz, CDCl₃): δ 7.69 (d, J=7.6 Hz, 1H), 7.60 (t, J=6.8 Hz,1H), 7.53 (t, J=8.0 Hz, 1H), 7.30 (m, 2H), 7.03 (s, 1H), 4.46 (q, J=6.8Hz, 2H), 2.37 (s, 3H) and 1.38 (t, J=6.8 Hz, 3H). MS: 462.25 (M+H)⁺.Yield: 26%.

Ethyl1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-2-yl)-1H-pyrazole-3-carboxylate(22.19-c)

¹H-NMR (400 MHz, CDCl₃): δ 8.52 (d, J=4.4 Hz, 1H), 7.77 (t, J=8.0 Hz,1H), 7.55 (t, J=7.6 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.29 (m, 2H), 7.25(m, 1H), 7.19 (m, 1H), 4.43 (q, J=7.2 Hz, 2H) and 1.39 (t, J=7.2 Hz,3H). MS: 380.20 (M+H)⁺. Yield: 40%.

Preparation of 22.20 (a-c):

These intermediates were prepared following the general procedurementioned in Scheme 18.

1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(6-methylpyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (22.20-a)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.44 (s, 1H), 7.87 (m, 1H), 7.64 (d, J=7.2Hz, 1H), 7.57 (m, 1H), 7.29 (m, 2H), 7.19 (m, 1H) and 2.50 (s, 3H). MS:366.15 (M+H)⁺. Yield: 59%.

1-(3-Fluoro-4-(trifluoromethyl)phenyl)-5-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (22.20-b)

¹H-NMR (400 MHz, DMSO-d₆): δ 7.93 (d, J=8.0 Hz, 1H), 7.80 (d, J=8.0 Hz,1H), 7.76 (m, 1H), 7.62 (m, 1H), 7.27 (m, 1H), 7.08 (m, 1H) and 2.63 (s,3H). MS: 432.09 (M−H)⁺. Yield: 83%.

1-(3-Fluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-2-yl)-1H-pyrazole-3-carboxylicAcid (22.20-c)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.45 (d, J=4.0 Hz, 1H), 7.90 (t, J=8.0 Hz,1H), 7.76 (m, 2H), 7.54 (d, J=7.2 Hz, 1H), 7.37 (m, 1H), 7.27 (d, J=8.0Hz, 1H) and 7.20 (s, 1H): LC-MS: 351.97 (M+H)⁺, 99.57%. Yield: 47%.

Preparation of 22.21 (a-c):

These intermediates were prepared following the general procedurementioned in Scheme 18.

Yields and the analytical data of the final compounds are set forth inTable 6.8.

TABLE 6.8 Tabulated data of the final compounds including the individualyields Yield NMR data (DMSO-d₆, 400 MHz), Comound No. Structure (%) LCMSunless otherwise specified 262

22 597.18 (M + H)⁺, 97.44% δ 8.81 (s, 1H), 8.45-8.46 (m, 1H), 7.83- 7.87(m, 1H), 7.58-7.65 (m, 2H), 7.28- 7.32 (m, 2H), 7.08-7.12 (m, 3H), 6.84-6.87 (m, 2H), 4.58-4.59 (m, 2H), 4.42- 4.45 (m, 2H), 3.84-3.87 (m, 1H),3.50- 3.54 (m, 1H), 2.50 (s, 3H), 2.20-2.23 (m, 2H) and 1.74-1.79 (m,2H) 263

26 663.10 (M − H)⁺, 98.09% δ 8.82 (s, 1H), 7.94-7.96 (m, 1H), 7.80- 7.83(m, 2H), 7.60-7.63 (m, 1H), 7.17- 7.19 (m, 2H), 7.09-7.11 (m, 2H), 6.85-6.89 (m, 2H), 4.60 (s, 2H), 4.44-4.45 (m, 2H), 3.86-3.89 (m, 1H),3.53-3.55 (m, 1H), 2.40 (s, 3H), 2.22-2.25 (m, 2H) and 1.75-1.81 (m, 2H)264

25 583.14 (M + H)⁺, 96.24% δ 8.81 (s, 1H), 8.47-8.48 (m, 1H), 7.92- 7.96(m, 1H), 7.79-7.81 (m, 2H), 7.57- 7.60 (m, 1H), 7.39-7.42 (m, 1H), 7.27-7.30 (m, 2H), 7.08-7.12 (m, 2H), 6.84- 6.87 (m, 2H), 4.58-4.59 (m, 2H),4.44- 4.45 (m, 2H), 3.84-3.88 (m, 1H), 3.50- 3.54 (m, 1H), 2.17-2.21 (m,2H) and 1.74-1.77 (m, 2H)

Preparation of4-ethoxy-2-methyl-3,4-dioxo-1-(pyridin-3-yl)but-1-en-1-olate LithiumSalt (23.23)

A solution of 3-propionylpyridine 23.22 (2 g, 14.8 mmol) in diethylether (20 mL) was cooled to −78° C. followed by addition of LiHMDS (1.0M in THF, 17 mL, 17.0 mmol). The resulting reaction mixture was stirredat −78° C. for 45 min followed by dropwise addition of diethyl oxalate(2.32 mL, 17.0 mmol) in about 30 min. The reaction mixture was then leftto stir at room temperature for 16 h. After completion of the reaction(TLC and MS monitoring), the solution was then cooled 0° C. and theresulting precipitate was filtered to get the desired product as anoff-white solid 23.23 (3.4 g, 98%), which was carried forward to thenext step without purification. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.41 (m,2H), 7.56 (d, J=7.60 Hz, 1H), 7.25 (d, J=7.60 Hz, 1H), 3.65 (q, J=7.20Hz, 2H), 3.36 (s, 3H) and 1.08 (t, J=6.8 Hz, 3H). MS: 236.10 (M+H)⁺.

General Procedure for the Preparation of Compounds 23.24 (a-b):

To an ice-cold solution of4-ethoxy-2-methyl-3,4-dioxo-1-(pyridin-3-yl)but-1-en-1-olate lithiumsalt 23.23 (1 eq) in IPA was added respective hydrazine hydrochloride (1eq) and TFA (2 eq). The resulting reaction mixture was warmed to roomtemperature and then stirred at 90° C. for 4-5 h. After completion ofthe reaction (TLC monitoring), the solvent was evaporated and theresidue was diluted with water and extracted with ethyl acetate (3times). The combined organics were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated. The crude waspurified over silica gel (100-200 M, 10-15% EtOAc-hexane) to get thedesired product 23.24 (a-b).

Ethyl1-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(23.24-a)

¹H-NMR (400 MHz, CDCl₃): δ 8.73 (m, 1H), 8.57 (s, 1H), 7.68 (m, 1H),7.60 (m, 3H), 7.02 (m, 1H), 4.45 (q, J=7.2 Hz, 2H), 2.33 (s, 3H) and1.18 (t, J=7.6 Hz, 3H). MS: 394.08 (M+H)⁺. Yield: 25%.

Ethyl4-methyl-5-(pyridin-3-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carboxylate(23.24-b)

¹H-NMR (400 MHz, CDCl₃): δ 8.62 (m, 1H), 8.49 (s, 1H), 7.69 (m, 1H),7.49 (m, 1H), 7.40 (m, 2H), 4.36 (q, J=6.8 Hz, 2H), 2.22 (s, 3H) and1.17 (t, J=6.8 Hz, 3H). MS: 362.13 (M+H)⁺. Yield: 22%.

General Procedure for the Preparation of Compounds 23.25 (a-b):

To an ice-cold solution of compound 23.24 (a-b) (1.0 eq) in EtOH wasadded dropwise an aqueous solution of sodium hydroxide (3.0 eq). Theresulting solution was stirred at room temperature for 4 h. Aftercompletion of the reaction (TLC monitoring), the solvent was evaporated,added H₂O to the residue followed by extraction with EtOAc (2×100 mL).The organic layer was discarded and the pH of the aqueous layer wasadjusted to ˜4 by adding 1N HCl. The resulting precipitate was filteredand dried under vacuum to get the desired product 23.25 (a-b) as a whitesolid.

1-(3-Fluoro-4-(trifluoromethyl)phenyl)-4-methyl-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (23.25-a)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.12 (br s, 1H), 8.64 (m, 1H), 8.50 (s,1H), 7.81 (t, J=8.0 Hz, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.48 (m, 2H), 7.23(d, J=8.0 Hz, 1H) and 2.21 (s, 3H). MS: 366.17 (M+H)⁺. Yield: 65%.

4-Methyl-5-(pyridin-3-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carboxylicAcid (23.25-b)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.07 (br s, 1H), 8.62 (m, 1H), 8.49 (s,1H), 7.69 (d, J=7.6 Hz, 1H), 7.46 (m, 1H), 7.36 (m, 2H) and 2.20 (s,3H). LCMS: 334.13 (M+H)⁺, 99.66%. Yield: 55%.

General Procedure for the Preparation of Final Compounds 23.26 (a-b):

To an ice-cold solution of carboxylic acids 23.25 (a-b) (1.0 eq), in DMF(2.0 mL) was added DIPEA (3.0 eq) and HATU (1.50 eq). The resultingmixture was stirred under nitrogen atmosphere at 0° C. for 15 minfollowed by addition of respective amines (1.20 eq). The reactionmixture was then stirred at room temperature for 16 h. After thecompletion of the reaction (TLC monitoring), the solution was dilutedwith ice-cold water (30 mL) followed by extraction with EtOAc (3×50 mL).The combined organics were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The cruderesidue was purified via prep-HPLC.

The yields and analytical data of the final compounds are set forth inTable 6.9.

TABLE 6.9 Tabulated data of the final compounds including the individualyields Compound Yield NMR data (DMSO-d₆, 400 MHz), No. Structure (%)LCMS unless otherwise specified 265

13 597.18 (M + H)⁺, 99.21% δ 8.82 (s, 1H), 8.64-8.66 (m, 1H), 8.53- 8.54(m, 1H), 7.75-7.80 (m, 2H), 7.46- 7.53 (m, 2H), 7.07-7.16 (m, 3H), 6.85-6.88 (m, 2H), 4.59-4.60 (m, 2H), 4.45- 4.48 (m, 1H), 4.10-4.13 (m, 1H),3.79- 3.85 (m, 1H), 3.51-3.57 (m, 1H), 2.36- 2.38 (m, 1H), 2.27-2.29 (m,1H), 2.09 (s, 3H), 1.80-1.84 (m, 1H) and 1.72- 1.75 (m, 1H) 266

12 565.14 (M + H)⁺, 99.90% δ 8.81 (s, 1H), 8.62-8.63 (m, 1H), 8.50- 8.51(m, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.47-7.49 (m, 1H), 7.29-7.31 (m, 2H),7.07-7.12 (m, 2H), 6.84-6.87 (m, 2H), 4.59 (s, 2H), 4.43-4.46 (m, 1H),4.12- 4.15 (m, 1H), 3.78-3.83 (m, 1H), 3.50- 3.53 (m, 1H), 2.26-2.30 (m,2H), 2.08 (s, 3H) and 1.71-1.83 (m, 2H)

General Procedure for the Preparation of 24.28 (a-d):

To an ice-cold solution of 1-benzylpiperidin-4-one 24.27 (1 eq) inacetic acid was added respective aryl amines (1.1 eq) and trimethylsilylcyanide (1.5 eq). The resulting reaction mass was stirred at RT for 18h. After completion of the reaction (TLC monitoring), the reaction masswas cooled to 0° C. and the pH adjusted to ˜10 using 5.0 N sodiumhydroxide solution. The aqueous part was extracted with DCM (3×250 mL).The combined organics were dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude was triturated with diethyl ether to get thedesired product 24.28 (a-d) as off white solid.

1-Benzyl-4-((4-fluorophenyl)amino)piperidine-4-carbonitrile (24.28-a)

¹H-NMR (400 MHz, CDCl₃): δ 7.32 (m, 5H), 6.91-6.94 (m, 4H), 3.55 (s,2H), 3.47 (br s, 1H), 2.81-2.84 (m, 2H), 2.39 (m, 2H), 2.21-2.24 (m, 2H)and 1.87-1.94 (m, 2H). LC-MS: 310.13 (M+H)⁺, 96.16%. Yield: 84%

1-Benzyl-4-((3,4-difluorophenyl)amino)piperidine-4-carbonitrile(24.28-b)

¹H-NMR (400 MHz, CDCl₃): δ 7.28 (m, 5H), 7.00 (m, 1H), 6.73 (m, 1H),6.61 (m, 1H), 3.58 (br s, 1H), 3.55 (s, 2H), 2.80 (m, 2H), 2.41 (m, 2H),2.26 (m, 2H) and 1.87 (m, 2H). LC-MS: 328.42 (M+H)+, 94.27%. Yield: 50%

1-Benzyl-4-((4-fluoro-3-methylphenyl)amino)piperidine-4-carbonitrile(24.28-c)

¹H-NMR (400 MHz, CDCl₃): δ 7.31 (m, 5H), 6.87 (m, 1H), 6.74 (m, 2H),3.55 (s, 2H), 3.40 (s, 1H), 2.81-2.84 (m, 2H), 2.39 (m, 2H), 2.23 (s,3H), 2.21 (m, 2H) and 1.87 (m, 2H). LC-MS: 324.40 (M+H)⁺, 92.13%. Yield:77%

1-Benzyl-4-((2,4-difluorophenyl)amino)piperidine-4-carbonitrile(24.28-d)

¹H-NMR (400 MHz, CDCl₃): δ 7.28 (m, 5H), 7.12 (m, 1H), 6.69 (m, 2H),3.71 (br s, 1H), 3.62 (s, 2H), 2.81 (m, 2H), 2.41 (m, 2H), 2.19 (m, 2H)and 1.91 (m, 2H). LC-MS: 328.26 (M+H)⁺, 95.96%. Yield: 36%

General Procedure for the Preparation of 24.29 (a-d):

To an ice-cold solution of 24.28 (a-d) (1.0 eq) was added 90% aqueoussulphuric acid and the resulting reaction mixture was stirred at roomtemperature for 16 h. After completion of the reaction (TLC monitoring),the reaction mass was cooled to 0° C. and the pH adjusted to ˜10 using5.0 N sodium hydroxide solution. The aqueous part was extracted withDCM. The combined organics were dried over anhydrous sodium sulphate,filtered and concentrated. The crude was triturated with diethyl etherto get the desired product 24.29 (a-d) as off-white solid.

1-Benzyl-4-(4-fluorophenylamino)piperidine-4-carboxamide (24.29-a)

¹H-NMR (400 MHz, CDCl₃): δ 7.23 (m, 5H), 6.87 (m, 3H), 6.55 (m, 2H),5.47 (br s, 1H), 3.93 (s, 1H), 3.48 (s, 2H), 2.72 (m, 2H), 2.28 (m, 2H),2.04 (m, 2H) and 1.86 (m, 2H). LCMS: 328.12 (M+H)+, 99.60%. Yield: 84%

1-Benzyl-4-((3,4-difluorophenyl)amino)piperidine-4-carboxamide (24.29-b)

¹H-NMR (400 MHz, CDCl₃): δ 7.30 (m, 5H), 6.88 (m, 1H), 6.78 (br s, 1H),6.42 (m, 1H), 6.29 (m, 1H), 5.51 (br s, 1H), 3.98 (s, 1H), 3.48 (s, 2H),2.73 (m, 2H), 2.28 (m, 2H), 2.04 (m, 2H) and 1.85 (m, 2H). LCMS: 346.14(M+H)⁺, 92.24%. Yield: 66%

1-Benzyl-4-((3-fluoro-4-methylphenyl)amino)piperidine-4-carboxamide(24.29-c)

¹H-NMR (400 MHz, DMSO-d₆): δ 7.24 (m, 5H), 7.18 (s, 1H), 7.02 (br s,1H), 6.81 (m, 1H), 6.45 (m, 1H), 6.35 (m, 1H), 5.34 (br s, 1H), 3.41 (s,2H), 2.50 (m, 2H), 2.24 (m, 2H), 2.09 (s, 3H), 1.95 (m, 2H) and 1.81 (m,2H). LCMS: 342.33 (M+H)⁺, 97.83%. Yield: 59%

1-Benzyl-4-((2,4-difluorophenyl)amino)piperidine-4-carboxamide (24.29-d)

¹H-NMR (400 MHz, DMSO-d₆): δ 7.20 (m, 6H), 7.10 (m, 1H), 7.07 (br s,1H), 6.82 (m, 1H), 6.46 (m, 1H), 4.78 (s, 1H), 3.41 (s, 2H), 2.52 (m,2H), 2.13 (m, 2H), 1.98 (m, 2H) and 1.83 (m, 2H). LCMS: 346.25 (M+H)⁺,96.72%. Yield: 46.9%

General Procedure for the Preparation of 24.30 (a-d):

A solution of compounds 24.29 (a-d) in triethylorthoformate and AcOH(3:1) was irradiated by microwave in a sealed tube to 190° C. for 2 h.The reaction mixture was diluted with water and extracted with EtOAc.The combined organics were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified over silicagel (100-200 M, 2-4% MeOH-DCM) to get the desired product 24.30 (a-d) asoff-white solid.

8-Benzyl-1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one(24.30-a)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.65 (s, 1H), 7.44 (m, 2H), 7.34 (m, 2H),7.13 (m, 5H), 3.41 (s, 2H), 2.66 (m, 2H), 2.41 (m, 2H) and 1.75 (m, 4H).MS: 338.22 (M+H)⁺. Yield: 48%.

8-Benzyl-1-(3,4-difluorophenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one(24.30-b)

LCMS: 356.29 (M+H)+, 82.22%. Yield: 22%.

8-Benzyl-1-(4-fluoro-3-methylphenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one(24.30-c)

MS: 352.13 (M+H)⁺. Yield: 31%.

8-benzyl-1-(2,4-difluorophenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one(24.30-d)

MS: 356.19 (M+H)⁺. Yield: 18%.

General Procedure for the Preparation of 24.31 (a-d):

To a solution of compounds 24.30 (a-d) (1.0 eq) in MeOH and AcOH (40:1,20 mL) was added Pd—C (w/w, 10 mol %) and the resulting solution wasstirred under hydrogen atmosphere (1 atm) at ambient temperature for 16h. The reaction mixture was filtered through diatomaceous earth (Celite)bed and the filtrate was concentrated under reduced pressure. Theresidue was purified over silica gel (basic alumina, 2-4% MeOH-DCM) toget the desired product 24.31 (a-d) as off-white solid.

1-(4-Fluorophenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one (24.31-a)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.79 (br s, 1H), 7.03 (m, 2H), 6.95 (m,2H), 4.56 (s, 2H), 3.37 (m, 3H), 2.95 (m, 2H), 2.33 (m, 2H) and 1.62 (m,2H). LCMS: 250.13 (M+H)⁺, 81.19%. Yield: 70%

1-(3,4-Difluorophenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one (24.31-b)

MS: 268.20 (M+H)⁺. Yield: 25%

1-(4-Fluoro-3-methylphenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one(24.31-c)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.58 (br s, 1H), 6.96 (m, 1H), 6.83 (m,2H), 4.52 (s, 2H), 3.40 (m, 1H), 3.17 (m, 2H), 2.83 (m, 2H), 2.15 (m,3H), 2.09 (m, 2H) and 1.49 (m, 2H). MS: 264.14 (M+H)⁺. Yield: 50%

1-(2,4-Difluorophenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one (24.31-d)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.66 (br s, 1H), 7.47 (m, 1H), 7.27 (m,1H), 7.08 (m, 1H), 4.51 (s, 2H), 3.12 (m, 1H), 2.81 (m, 2H), 1.83 (m,4H) and 1.40 (m, 2H). LCMS: 268.12 (M+H)⁺, 92.83%. Yield: 90%

Preparation of 3-chloroindolin-2-one (25.33)

To an ice-cold solution of nitrostyrene 25.32 (5.0 g, 335.55 mmol) inDCM was added acetyl chloride (5.0 mL, 67.11 mmol) and FeCl₃ (13.0 g,67.11 mmol). The resulting reaction mass was stirred at 0° C. for 5 h.After completion of reaction (TLC monitoring), added 0.1M HCl (100 mL)and stirred at RT for 16 h. The resulting reaction mixture was extractedwith DCM (3×100 mL). The combined organics were washed with brine, driedover anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified over silica gel (100-200 M, 25% EtOAc/hexane) to get thedesired product 25.33 (2.4 g, 43%) as off-white solid. ¹H-NMR (400 MHz,DMSO-d₆): δ 10.76 (br s, 1H), 7.35 (d, J=7.6 Hz, 1H), 7.27 (t, J=7.6 Hz,1H), 7.03 (t, J=7.2 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H) and 5.57 (s, 1H).LCMS: 166.07 (M−H)⁺, 99.70%.

Preparation of 3-(4-benzylpiperazin-1-yl) indolin-2-one (25.34)

To a solution of 3-chloroindolin-2-one 25.33 (1.0 g, 5.97 mmol) in ACN(10 mL) was added potassium carbonate (1.23 g, 8.96 mmol) and1-benzylpiperazine (1.16 g, 6.57 mmol). The resulting reaction mixturewas heated at 80° C. for 16 h. After completion of the reaction (TLCmonitoring), the solvent was evaporated and the residue was diluted withwater and extracted with ethyl acetate (3 times). The combined organicswere washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude was purified over silica gel (100-200 M, 40%EtOAc-hexane) to get the desired product 25.34 (0.62 g, 31%). ¹H-NMR(400 MHz, DMSO-d₆): δ 7.84 (br s, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.20 (m,6H), 7.01 (t, J=7.6 Hz, 1H), 6.80 (d, J=7.6 Hz, 1H), 4.29 (s, 1H), 3.51(s, 2H), 2.88 (m, 2H), 2.65 (m, 2H) and 2.49 (m, 4H). MS: 308.21 (M+H)⁺.

Preparation of 3-(piperazin-1-yl) indolin-2-one (25.35)

To a solution of 3-(4-benzylpiperazin-1-yl) indolin-2-one 25.34 (0.30 g,0.98 mmol) in MeOH and AcOH (40:1, 10 mL) was added Pd—C (w/w, 10 mol %)and the resulting solution was stirred under hydrogen atmosphere (1 atm)at ambient temperature for 16 h. The reaction mixture was filteredthrough diatomaceous earth (Celite) bed and the filtrate wasconcentrated under reduced pressure to get the desired product 25.35(0.16 g, 76%) as off-white solid. ¹H-NMR (400 MHz, DMSO-d₆): δ 10.32 (brs, 1H), 7.23 (d, J=7.2 Hz, 1H), 7.17 (m, 1H), 6.93 (t, J=6.8 Hz, 1H),6.71 (d, J=8.0 Hz, 1H), 4.25 (s, 1H), 2.53 (m, 1H), 2.50 (m, 4H), 2.38(m, 2H) and 1.87 (m, 2H). MS: 218.16 (M+H)⁺.

Preparation of tert-butyl 4-amino-2-methylpiperidine-1-carboxylate(26.37)

To a solution of tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate 26.36(2.0 g, 9.38 mmol) in methanolic ammonia (˜4N, 200 mL) was added Pd/C(10 mol %, 0.2 g). The resulting reaction mixture was stirred at 50 PSIfor 60 h under hydrogen atmosphere. After completion of the reaction(TLC monitoring), the reaction mass was filtered through diatomaceousearth (Celite) bed. The filtrate was dried under reduced pressure to getdesired product 26.37 (2.0 g, quantitative yield) as semi solid. MS:215.17 (M+H)⁺.

Preparation of tert-butyl2-methyl-4-((2-nitrophenyl)amino)piperidine-1-carboxylate (26.38)

To an ice-cold solution of tert-butyl4-amino-2-methylpiperidine-1-carboxylate 26.37 (1.7 g, 7.93 mmol) in DMF(10 mL) was added DIPEA (2.0 mL, 11.89 mmol) and 1-fluoro-2-nitrobenzene(1.2 g, 7.93 mmol). The resulting reaction mixture was heated at 80° C.for 16 h. After completion of the reaction (TLC monitoring), the solventwas evaporated and the residue was diluted with water and extracted withethyl acetate (3 times). The combined organics were washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated. The crude waspurified over silica gel (100-200 M, 10% EtOAc-hexane) to get thedesired product 26.38 (1.3 g, 50%). ¹H-NMR (400 MHz, CDCl₃): δ 8.38 (m,1H), 8.18 (d, J=8.8 Hz, 1H), 7.42 (t, J=7.2 Hz, 1H), 6.82 (d, J=8.8 Hz,1H), 6.40 (t, J=7.6 Hz, 1H), 4.30 (m, 1H), 3.90 (m, 1H), 3.21 (m, 2H),1.95 (m, 2H), 1.77 (m, 2H), 1.47 (s, 9H) and 1.30 (d, J=6.8 Hz, 3H).LCMS: 334.21 (M−H)⁺, 89.85%.

Preparation of tert-butyl4-((2-aminophenyl)amino)-2-methylpiperidine-1-carboxylate (26.39)

To a solution of tert-butyl2-methyl-4-((2-nitrophenyl)amino)piperidine-1-carboxylate 26.38 (1.30 g,3.87 mmol) in MeOH (10 mL) was added Pd—C (w/w, 10 mol %) and theresulting solution was stirred under hydrogen atmosphere (1 atm) atambient temperature for 16 h. The reaction mixture was filtered throughdiatomaceous earth (Celite) bed and the filtrate was concentrated underreduced pressure to get the desired product 26.39 (1.15 g, quantitative)as off-white solid. MS: 306.20 (M+H)⁺.

Preparation of tert-butyl2-methyl-4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate(26.40)

To an ice-cold solution of tert-butyl4-((2-aminophenyl)amino)-2-methylpiperidine-1-carboxylate 26.39 (0.50 g,1.64 mmol) in THF (20 mL) was added Et₃N (0.34 mL, 2.46 mmol) andtriphosgene (0.59 g, 1.96 mmol). The resulting reaction mixture washeated at RT for 4 h. After completion of the reaction (TLC monitoring),the solvent was evaporated and the residue was diluted with water andextracted with ethyl acetate (3 times). The combined organics werewashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude was purified over silica gel (100-200 M, 40%EtOAc-hexane) to get the desired product 26.40 (0.5 g, 90%). ¹H-NMR (400MHz, DMSO-d₆): δ 10.86 (br s, 1H), 7.23 (m, 1H), 6.97 (m, 3H), 4.34 (m,1H), 3.64 (m, 2H), 2.27 (m, 1H), 1.94 (m, 2H), 1.72 (m, 2H), 1.43 (s,9H) and 1.35 (m, 3H). MS: 330.22 (M−H)⁺.

Preparation of1-(2-methylpiperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-oneHydrochloride Salt (26.41)

An ice-cold solution of tert-butyl2-methyl-4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate26.40 (0.25 g, 0.75 mmol) in 1,4-dioxane-HCl (˜4N, 10 mL) was stirred atRT for 2 h. After completion of the reaction (TLC monitoring), thereaction mass was dried under reduced pressure to get desired product26.41 (0.2 g, quantitative) as off-white solid. MS: 232.12 (M+H)⁺.

General Procedure for the Preparation of 27.3 (a-b):

General Method J:

To an ice-cold solution of compound 27.1-a or b (1.0 eq) in THF wasadded Et₃N (2.0 eq) and 1,1′-thiocarbonyldiimidazole 27.2 (1.5 eq). Theresulting reaction mixture was stirred at RT for 4 h. After completionof the reaction (TLC monitoring), the solvent was evaporated and theresidue was diluted with water and extracted with ethyl acetate (3times). The combined organics were washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated. The crude was purified oversilica gel (100-200 M, 40-45% EtOAc-hexane) to get the desired product27.3 (a-b).

tert-Butyl4-(6,7-difluoro-2-thioxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate(27.3a)

LCMS: 268.29 (M−H)⁺, 93.54%. Yield: 47%

tert-Butyl4-(5,6,7-trifluoro-2-thioxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate(27.3b)

¹H-NMR (400 MHz, DMSO-d₆): δ 12.14 (br s, 1H), 6.37-6.42 (m, 1H),4.01-4.07 (m, 1H), 3.84-3.89 (m, 2H), 2.67-2.71 (m, 2H), 1.71-1.74 (m,2H), 1.42-1.43 (m, 2H) and 1.38 (s, 9H). MS: 386.05 (M−H)⁺, Yield: 72%.

General Procedure for the Preparation of 27.4 (a-b):

This compound was prepared following the general method M (Scheme 8).

6,7-Difluoro-1-(piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazole-2-thioneHydrochloride (27.4a)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.24 (br s, 1H), 9.06 (br s, 1H), 8.48 (brs, 1H), 7.27-7.34 (m, 1H), 7.01-7.02 (s, 1H), 5.45-5.55 (m, 1H),3.56-3.61 (m, 4H), 3.14-3.17 (m, 2H) and 1.93-1.96 (m, 2H). LCMS: 260.30(M+H)⁺, 91.35%. Yield: 98%.

5,6,7-Trifluoro-1-(piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazole-2-thioneHydrochloride (27.4b)

MS: 287.99 (M+H)⁺. Yield: 58%.

Preparation of tert-butyl4-((2,3-difluoro-6-nitrophenyl)amino)-2-methylpiperidine-1-carboxylate(28.3)

To an ice-cold solution of tert-butyl4-amino-2-methylpiperidine-1-carboxylate 28.2 (1.06 g, 4.97 mmol) inacetonitrile (15 mL) was added DIPEA (1.0 mL, 5.65 mmol) and1,2,3-trifluoro-4-nitrobenzene 28.1 (0.8 g, 4.52 mmol). The resultingreaction mixture was stirred at RT for 3 h. After completion of thereaction (TLC monitoring), the reaction mass was diluted with ice-coldwater (100 mL) and extracted with EtOAc (100 mL×3 times). The combinedorganics were washed with brine, dried over anhydrous Na₂SO₄, filteredand concentrated. The crude was purified over silica gel (100-200 M,10-15% EtOAc-hexane) to get the desired product 28.3 (1.4 g, Yield: 85%)as pale yellow solid. ¹H-NMR (400 MHz, CDCl₃): δ 8.26 (br s, 1H),8.01-8.05 (m, 1H), 6.47-6.54 (m, 1H), 4.20-4.24 (m, 2H), 3.87-3.93 (m,1H), 3.18-3.25 (m, 1H), 2.00-2.09 (m, 2H), 1.71-1.76 (m, 2H), 1.46 (s,9H) and 1.22 (d, J=7.2 Hz, 3H). LCMS: 370.34 (M−H)⁺, 93.68%.

Preparation of tert-butyl4-((6-amino-2,3-difluorophenyl)amino)-2-methylpiperidine-1-carboxylate(28.4)

To a solution of tert-butyl4-((2,3-difluoro-6-nitrophenyl)amino)-2-methylpiperidine-1-carboxylate28.3 (1.4 g, 3.78 mmol) in EtOAc (40 mL) was added Pd—C (0.14 g, 0.38mmol, w/w, 10 mol %) and the resulting solution was stirred underhydrogen atmosphere (1 atm) at ambient temperature for 16 h. Thereaction mixture was filtered through a diatomaceous earth (Celite) bedand the filtrate was concentrated under reduced pressure to get thedesired product 28.4 (1.1 g, Yield: 91.0%) as viscous liquid. ¹H-NMR(400 MHz, DMSO-d₆): δ 6.57-6.64 (m, 1H), 6.32-6.36 (m, 1H), 4.76 (br s,2H), 3.94-3.96 (m, 1H), 3.74-3.78 (m, 1H), 3.48-3.51 (m, 1H), 3.30-3.34(m, 1H), 3.20-3.24 (m, 1H), 1.71-1.82 (m, 2H), 1.45-1.48 (m, 2H), 1.37(s, 9H) and 1.14 (d, J=6.8 Hz, 3H). LCMS: 342.11 (M+H)⁺, 94.16%. Yield:92%.

General Procedure for the Preparation of 28.5 (a-b):

To an ice-cold solution of compound 17 (1.0 eq) in THF was added Et₃N(2.0 eq) and triphosgene (1.5 eq, for 18a) or1,1′-thiocarbonyldiimidazole (1.5 eq, for 18b). The resulting reactionmixture was stirred at RT for 4 h. After completion of the reaction (TLCmonitoring), the solvent was evaporated and the residue was diluted withwater and extracted with ethyl acetate (3 times). The combined organicswere washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude was purified over silica gel (100-200 M, 40-45%EtOAc-hexane) to get the desired product 18 (a-b).

tert-Butyl4-(6,7-difluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-2-methylpiperidine-1-carboxylate(28.5-a)

¹H-NMR (400 MHz, CDCl₃): δ 9.45 (br s, 1H), 7.06-7.08 (m, 1H), 6.99-7.04(m, 1H), 4.70-4.72 (m, 1H), 3.99-4.02 (m, 1H), 3.85-3.89 (m, 1H),3.73-3.74 (m, 1H), 3.35-3.43 (m, 1H), 2.19-2.26 (m, 2H), 1.84-1.90 (m,1H), 1.30-1.33 (m, 9H) and 1.24 (d, J=6.4 Hz, 3H). MS: 366.33 (M−H)⁺.Yield: 56%.

tert-Butyl4-(6,7-difluoro-2-thioxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-2-methylpiperidine-1-carboxylate(28.5-b)

LCMS: 384.15 (M+H)⁺, 89.21%. Yield: 71%.

General Procedure for the Preparation of 28.6 (a-b):

These compounds were prepared following the general method M (Scheme 8).

6,7-Difluoro-1-(2-methylpiperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-oneHydrochloride (28.6-a)

¹H-NMR (400 MHz, DMSO-d₆): δ 11.33 (br s, 1H), 9.41-9.43 (m, 1H), 8.64(br s, 1H), 7.01-7.05 (m, 1H), 6.78-6.81 (m, 1H), 4.58-4.64 (m, 1H),3.52-3.56 (m, 2H), 2.42-3.49 (m, 1H), 2.17-2.20 (m, 1H), 1.90-1.99 (m,3H) and 1.27 (d, J=6.4 Hz, 3H). MS: 266.0 (M−H)⁺. Yield: 92%.

6,7-Difluoro-1-(2-methylpiperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazole-2-thioneHydrochloride (28-6b)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.35 (br s, 1H), 9.26 (br s, 1H), 8.60 (brs, 1H), 7.26-7.33 (m, 1H), 7.01-7.03 (s, 1H), 5.48-5.55 (m, 1H),3.28-3.38 (m, 4H), 3.22-3.24 (m, 1H), 1.92-1.95 (m, 2H) and 1.24 (d,J=6.4 Hz, 3H). MS: 284.0 (M+H)⁺. Yield: 67%.

General Procedure for the Preparation of 29.2 (a-i)

General Method K:

To an ice-cold solution of compound 29.1 (a-i) (1.0 eq) in THF was addedLiHMDS (1.0 M in THF, 2.5 eq) dropwise. The resulting reaction mixturewas stirred at 0° C. for 15 min, followed by addition of boc anhydride(1.1 eq). The reaction mixture was warmed to RT and stirred for 4-5 h.After completion of reaction (TLC monitoring), reaction mass cooled to0° C. and diluted with brine solution. The organic layer was extractedwith EtOAc (3 times). The combined layer was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crude waspurified over silica gel (100-200M), elution with 5% EtOAc/hexane to getdesired product 29.2 (a-i).

tert-Butyl (2-bromo-3,4-difluorophenyl)carbamate (29.2a)

¹H-NMR (400 MHz, CDCl₃): δ 7.91-7.92 (m, 1H), 7.11-7.18 (m, 1H),6.87-6.95 (m, 1H) and 1.53 (s, 9H). MS: 306.06 (M−H)⁺. Yield: 41%.

tert-Butyl (2-bromo-4,5-difluorophenyl)carbamate (29.2b)

¹H-NMR (400 MHz, CDCl₃): δ 8.12-8.17 (m, 2H), 7.32-7.36 (m, 1H) and 1.54(s, 9H). LCMS: 306.09 (M−H)⁺, 94.59%. Yield: 82%.

tert-Butyl (2-bromo-4-(trifluoromethyl)phenyl)carbamate (29.2c)

¹H-NMR (400 MHz, CDCl₃): δ 8.31-8.36 (m, 1H), 7.76-7.78 (m, 1H),7.52-7.54 (m, 1H), 7.12-7.16 (m, 1H) and 1.54 (s, 9H). MS: 338.03(M−H)⁺. Yield: 71%.

tert-Butyl (2-bromo-5-(trifluoromethyl)phenyl)carbamate (29.2d)

¹H-NMR (400 MHz, CDCl₃): δ 8.51 (s, 1H), 7.61 (d, J=8.4 Hz, 1H),7.10-7.15 (m, 2H) and 1.54 (s, 9H). LCMS: 338.10 (M−H)⁺, 99.23%. Yield:85%.

tert-Butyl (2-bromo-4-fluoro-5-(trifluoromethyl)phenyl)carbamate (29.2e)

¹H-NMR (400 MHz, CDCl₃): δ 8.47-8.48 (m, 1H), 7.39 (d, J=8.8 Hz, 1H),6.64-6.96 (m, 1H) and 1.54 (s, 9H). LCMS: 356.05 (M−H)⁺, 98.92%. Yield:82%.

tert-Butyl (2-bromo-5-chloro-4-fluorophenyl)carbamate (29.2f)

¹H-NMR (400 MHz, CDCl₃): δ 8.29-8.31 (m, 1H), 7.26-7.33 (m, 1H), 6.86(s, 1H) and 1.53 (s, 9H). LCMS: 322.01 (M−H)⁺, 96.73%. Yield: 97%.

tert-Butyl (2-bromo-5-fluorophenyl)carbamate (29.2g)

¹H-NMR (400 MHz, CDCl₃): δ 8.00-8.03 (m, 1H), 7.41-7.45 (m, 1H), 7.03(br s, 1H), 6.63-6.65 (m, 1H) and 1.53 (s, 9H). LCMS: 288.16 (M−H)⁺,99.03%. Yield: 40%.

tert-Butyl (2-bromo-3-fluorophenyl)carbamate (29.2h)

¹H-NMR (400 MHz, CDCl₃): δ 7.96 (d, J=8.4 Hz, 1H), 7.25-7.29 (m, 1H),7.02 (br s, 1H), 6.79 (d, J=7.2 Hz, 1H) and 1.53 (s, 9H). LCMS: 287.93(M−H)⁺, 95.02%. Yield: 15%.

tert-Butyl (2-bromo-4-fluorophenyl)carbamate (29.2i)

¹H-NMR (400 MHz, CDCl₃): δ 7.97-8.01 (m, 1H), 7.48-7.52 (m, 1H), 7.06(br s, 1H), 7.80-7.85 (m, 1H) and 1.54 (s, 9H). LCMS: 288.20 (M−H)⁺,96.13%. Yield: 25%.

General Procedure for the Preparation of 29.4 (a-i):

General Method L:

To an ice-cold solution of compound 29.2 (a-i) (1.0 eq) in THF was addedMeLi (1.6 M in diethyl ether, 1.2 eq) dropwise under argon atmosphere.The resulting reaction mixture was stirred at 0° C. for 30 min. Aftercooling the reaction mass at −78° C., tert-BuLi (2.0 eq, 1.5 M in THF)was added dropwise and stirring continued for 1 h. A solution oftert-butyl 4-oxopiperidine-1-carboxylate 29.3 (1.0 eq) in THF was addedand the resulting reaction mixture was allowed to warm-up to RT.Potassium tert-butoxide (0.05 eq) was added and stirred for 16 h at RT.After completion of reaction (TLC monitoring), reaction mass cooled to0° C. and diluted with brine solution. The organic layer was extractedwith EtOAc (3 times). The combined layer was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crude waspurified over silica gel (100-200M), elution with 15-20% EtOAc/hexane toget desired product 29.4 (a-i).

tert-Butyl5,6-difluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,4′-piperidine]-1′-carboxylate(29.4a)

¹H-NMR (400 MHz, CDCl₃): δ 8.12 (s, 1H), 7.25 (s, 1H), 7.03-7.07 (m,1H), 3.70-3.73 (m, 2H), 3.09-3.15 (m, 2H), 2.84-2.86 (m, 2H), 1.72-1.77(m, 2H) and 1.52 (s, 9H). MS: 353.10 (M−H)⁺. Yield: 34%.

tert-Butyl6,7-difluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,4′-piperidine]-1′-carboxylate(29.4b)

¹H-NMR (400 MHz, CDCl₃): δ 7.84 (s, 1H), 6.93-6.98 (m, 1H), 6.65-6.69(m, 1H), 4.05-4.10 (m, 2H), 3.29-3.30 (m, 2H), 2.04-2.10 (m, 2H),1.83-1.90 (m, 2H) and 1.56 (s, 9H). MS: 353.18 (M−H)⁺. Yield: 50%.

tert-Butyl2-oxo-6-(trifluoromethyl)-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,4′-piperidine]-1′-carboxylate(29.4c)

¹H-NMR (400 MHz, CDCl₃): δ 8.09 (br s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.37(s, 1H), 6.90 (d, J=8.4 Hz, 1H), 4.09-4.13 (m, 2H), 3.30-3.33 (m, 2H),2.11-2.14 (m, 2H), 1.94-1.98 (m, 2H) and 1.55 (s, 9H). LCMS: 385.23(M−H)⁺, 94.97%. Yield: 32%.

tert-Butyl2-oxo-7-(trifluoromethyl)-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,4′-piperidine]-1′-carboxylate(29.4d)

¹H-NMR (400 MHz, CDCl₃): δ 8.25 (br s, 1H), 7.34 (d, J=8.4 Hz, 1H),7.23-7.26 (m, 1H), 7.08 (s, 1H), 4.00-4.12 (m, 2H), 3.26-3.34 (m, 2H),2.10-2.14 (m, 2H), 1.97-1.99 (m, 2H) and 1.48 (s, 9H). LCMS: 385.33(M−H)⁺, 89.02%. Yield: 62%.

tert-Butyl6-fluoro-2-oxo-7-(trifluoromethyl)-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,4′-piperidine]-1′-carboxylate(29.4e)

¹H-NMR (400 MHz, CDCl₃): δ 8.90 (br s, 1H), 7.08 (d, J=5.6 Hz, 1H),6.99-7.01 (m, 1H), 4.09-4.12 (m, 2H), 3.49-3.42 (m, 2H), 2.10-2.13 (m,2H), 1.89-1.95 (m, 2H) and 1.54 (s, 9H). LCMS: 403.32 (M−H)⁺, 94.74%.Yield: 22%.

tert-Butyl7-chloro-6-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,4′-piperidine]-1′-carboxylate(29.4f)

¹H-NMR (400 MHz, CDCl₃): δ 8.40 (br s, 1H), 6.87-6.99 (m, 2H), 4.09-4.12(m, 2H), 3.18-3.24 (m, 2H), 2.04-2.11 (m, 2H), 1.84-1.92 (m, 2H) and1.58 (s, 9H). LCMS: 369.32 (M−H)⁺, 99.36%. Yield: 47%.

tert-Butyl7-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,4′-piperidine]-1′-carboxylate(29.4g)

¹H-NMR (400 MHz, CDCl₃): δ 7.53 (br s, 1H), 7.06-7.09 (m, 1H), 6.76-6.80(m, 1H), 6.52-6.55 (m, 1H), 4.09-4.13 (m, 2H), 3.28-3.30 (m, 2H),2.04-2.07 (m, 2H), 1.91-1.94 (m, 2H) and 1.49 (s, 9H). MS: 335.30(M−H)⁺. Yield: 8%.

tert-Butyl5-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,4′-piperidine]-1′-carboxylate(29.4h)

MS: 335.30 (M−H)⁺. Yield: 10%.

tert-Butyl6-fluoro-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,4′-piperidine]-1′-carboxylate(29.4i)

MS: 335.17 (M−H)⁺. Yield: 12%.

General Procedure for the Preparation of 29.5 (a-i):

General Method-M:

An ice-cold solution of compound 28 (a-i) in 10% TFA-DCM was stirred atRT for 2 h. After completion of the reaction (TLC monitoring), thereaction mass was dried under reduced pressure. The crude was trituratedwith diethyl ether to get desired product 29 (a-i) as off solid.

5,6-Difluorospiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one(29.5a): Intermediate-12

¹H-NMR (400 MHz, DMSO-d₆): δ 10.64 (s, 1H), 8.53-8.66 (m, 1H), 7.39-7.46(m, 1H), 6.74-6.76 (m, 1H), 3.32-3.35 (m, 2H), 3.19-3.22 (m, 2H),2.39-2.43 (m, 2H) and 2.26-2.30 (m, 2H). LCMS: 253.99 (M−H)⁺, 91.53%.Yield: 90%.

6,7-Difluorospiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one(29.5b): Intermediate-13

¹H-NMR (400 MHz, DMSO-d₆): δ 10.56 (s, 1H), 8.72-8.79 (m, 1H), 7.31-7.40(m, 1H), 6.69-6.94 (m, 1H), 3.32-3.35 (m, 2H), 3.16-3.22 (m, 2H) and2.15-2.25 (m, 4H). MS: 255.21 (M+H)⁺. Yield: 78%.

6-(Trifluoromethyl)spiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one(29.5c): Intermediate-14

¹H-NMR (400 MHz, DMSO-d₆): δ 10.82 (s, 1H), 8.46 (br s, 1H), 7.69-7.71(m, 1H), 7.49 (s, 1H), 7.10-7.12 (m, 1H), 3.33-3.37 (m, 2H), 3.16-3.18(m, 2H) and 2.21-2.31 (m, 4H). LCMS: 285.24 (M−H)⁺, 99.24%. Yield: 95%.

7-(Trifluoromethyl)spiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one(29.5d): Intermediate-15

¹H-NMR (400 MHz, DMSO-d₆): δ 10.91 (s, 1H), 9.13-9.14 (m, 1H), 7.43-7.52(m, 2H), 7.22 (s, 1H), 3.34-3.38 (m, 2H), 3.18-3.22 (m, 2H) and2.23-2.24 (m, 4H). LCMS: 286.91 (M+H)⁺, 97.48%. Yield: 95%.

6-Fluoro-7-(trifluoromethyl)spiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one(29.5e): Intermediate-16

¹H-NMR (400 MHz, DMSO-d₆): δ 10.70 (s, 1H), 8.60 (br s, 1H), 7.48-7.51(m, 1H), 7.24-7.25 (m, 1H), 3.34-3.37 (m, 2H), 3.16-3.20 (m, 2H) and2.23-2.28 (m, 4H). LCMS: 304.91 (M+H)⁺, 97.69%. Yield: 83%.

7-Chloro-6-fluorospiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one(29.5f): Intermediate-17

¹H-NMR (400 MHz, DMSO-d₆): δ 10.56 (s, 1H), 8.38-8.48 (m, 1H), 7.37-7.39(m, 1H), 7.05-7.07 (m, 1H), 3.35-3.38 (m, 2H), 3.13-3.15 (m, 2H) and2.19-2.21 (m, 4H). LCMS: 269.04 (M−H)⁺, 99.39%. Yield: 93%.

7-Fluorospiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one (29.5g):Intermediate-18

¹H-NMR (400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 8.34-8.38 (m, 1H), 7.22-7.24(m, 1H), 6.92-6.93 (m, 1H), 6.71-6.73 (m, 1H), 3.35-3.40 (m, 2H),3.13-3.16 (m, 2H) and 2.17-2.21 (m, 4H). MS: 237.0 (M+H)⁺. Yield: 96%.

5-Fluorospiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one (29.5h):Intermediate-19

MS: 235.04 (M−H)⁺. Yield: 80%.

6-Fluorospiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one (29.5i):Intermediate-20

MS: 235.10 (M−H)⁺. Yield: 78%.

Preparation of tert-butyl (2-bromo-4-(trifluoromethyl)phenyl)carbamate(29.2d)

This compound was prepared following the general method K (Scheme 29).¹H-NMR (400 MHz, CDCl₃): δ 8.31-8.36 (m, 1H), 7.76-7.78 (m, 1H),7.52-7.54 (m, 1H), 7.12-7.16 (m, 1H) and 1.54 (s, 9H). MS: 338.03(M−H)⁺. Yield: 71%

Preparation of tert-butyl2′-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,4′-piperidine]-1′-carboxylate(30.2)

This compound was prepared following the general method L (Scheme 29).MS: 399.38 (M−H)⁺. Yield: 12%.

Preparation of2′-methyl-6-(trifluoromethyl)spiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one(30.3)

This compound was prepared following the general method-M (Scheme 29).¹H-NMR (400 MHz, DMSO-d₆): δ 10.84 (s, 1H), 8.58 (br s, 1H), 7.70-7.72(m, 1H), 7.49-7.53 (m, 1H), 7.11-7.13 (m, 1H), 3.35-3.38 (m, 2H),3.16-3.22 (m, 2H), 2.28-2.30 (m, 1H), 2.21-2.23 (m, 2H) and 1.27 (d,J=6.4 Hz, 3H). LCMS: 299.13 (M−H)⁺. Yield: 96%.

General Procedure for the Preparation of 31.2 (a-b):

General Method N:

To a solution of compound 31.1 (a-b) (1.0 eq) in DMF was added Cs₂CO₃(1.5 eq) and methyl iodide (1.5 eq). The resulting reaction mixture wasstirred for 16 h at RT. After completion of reaction (TLC monitoring),reaction mass was diluted with ice-cold water and extracted with EtOAc(3 times). The combined layer was washed with ice-water and brinesolution respectively and dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude was purified over silicagel (100-200M), elution with 20-30% EtOAc/hexane to get desired product31.2 (a-b).

tert-Butyl5,6-difluoro-1-methyl-2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,4′-piperidine]-1′-carboxylate(31.2a)

¹H-NMR (400 MHz, CDCl₃): δ 7.08-7.18 (m, 1H), 6.64-6.66 (m, 1H),4.06-4.14 (m, 2H), 3.37 (s, 3H), 3.19-3.25 (m, 2H), 2.25-2.31 (m, 2H),2.02-2.06 (m, 2H) and 1.45 (s, 9H). MS: 369.12 (M+H)⁺. Yield: 72%.

tert-Butyl1-methyl-2-oxo-6-(trifluoromethyl)-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,4′-piperidine]-1′-carboxylate(31.2b)

¹H-NMR (400 MHz, CDCl₃): δ 7.60-7.63 (m, 1H), 7.37 (s, 1H), 6.99-7.05(m, 1H), 4.10-4.14 (m, 2H), 3.43 (s, 3H), 3.24-3.29 (m, 2H), 2.06-2.09(m, 2H), 19.91-1.98 (m, 2H) and 1.48 (s, 9H). LCMS: 401.16 (M+H)⁺,96.95%. Yield: 70%.

General Procedure for the Preparation of 31.3 (a-b):

These compounds were prepared following the general method M (Scheme29).

5,6-Difluoro-1-methylspiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one(31.3a): Intermediate-22

¹H-NMR (400 MHz, DMSO-d₆): δ 8.74-8.84 (m, 1H), 7.53-7.55 (m, 1H), 7.01(s, 1H), 3.74-4.02 (m, 3H), 2.88-3.30 (m, 5H), and 2.29-2.32 (m, 3H).MS: 269.06 (M+H)⁺. Yield: 78%.

1-Methyl-6-(trifluoromethyl)spiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one(31.3b): Intermediate-23

¹H-NMR (400 MHz, DMSO-d₆): δ 8.48 (br s, 1H), 7.80 (d, J=8.8 Hz, 1H),7.55 (s, 1H), 7.34 (d, J=8.8 Hz, 1H), 3.35-3.45 (m, 5H), 3.16-3.18 (m,2H) and 2.23-2.35 (m, 4H). LCMS: 301.07 (M+H)⁺, 97.15%. Yield: 95%.

General Procedure for the Preparation of 32.3(a-b):

To an ice-cold solution of tert-butyl 4-aminopiperidine-1-carboxylate32.2 (1.0 eq) in ACN was added DIPEA (1.5 eq) and the respective nitrocompounds 32.1(a-b) (1.0 eq). The resulting reaction mixture was stirredat RT for 2-3 h. After completion of the reaction (TLC monitoring), thereaction mass was diluted with ice-cold water and extracted with EtOAc(3 times). The combined organics were washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated. The crude was purified oversilica gel (100-200 M, 10-15% EtOAc-hexane) to get the desired product32.3(a-b).

tert-Butyl 4-((2-fluoro-6-nitrobenzyl)amino)piperidine-1-carboxylate(32.3a)

¹H-NMR (400 MHz, CDCl₃): δ 7.69-7.71 (m, 1H), 7.32-7.43 (m, 2H),4.01-4.02 (m, 4H), 2.83-2.89 (m, 2H), 2.60-2.65 (m, 1H), 1.83-1.85 (m,2H), 1.44 (s, 9H) and 1.25-1.31 (m, 3H). LCMS: 354.33 (M+H)⁺, 97.42%.Yield: 47%.

tert-Butyl 4-((4-fluoro-2-nitrobenzyl)amino)piperidine-1-carboxylate(32.3b)

¹H-NMR (400 MHz, CDCl₃): δ 7.65-7.68 (m, 2H), 7.28-7.32 (m, 1H),4.00-4.02 (m, 4H), 2.78-2.84 (m, 2H), 2.62-2.65 (m, 1H), 1.83-1.86 (m,2H), 1.45 (s, 9H) and 1.25-1.29 (m, 3H). LCMS: 354.33 (M+H)⁺, 98.63%.Yield: 54%.

General Procedure for the Preparation of 32.4(a-b):

To a solution of compound 32.3(a-b) (1.0 eq) in EtOAc were added Pd—C(w/w, 10 mol %) and the resulting solution was stirred under hydrogenatmosphere (1 atm) at ambient temperature for 16 h. The reaction mixturewas filtered through a diatomaceous earth (Celite) bed and the filtratewas concentrated under reduced pressure to get the desired product 32.4(a-b).

tert-Butyl 4-((2-amino-6-fluorobenzyl)amino)piperidine-1-carboxylate(32.4a)

¹H-NMR (400 MHz, DMSO-d₆): δ 6.89-6.95 (m, 1H), 6.41-6.43 (m, 1H),6.26-6.60 (m, 1H), 5.54 (br s, 2H), 3.77-3.80 (m, 2H), 3.68 (s, 2H),2.78-2.81 (m, 2H), 2.63-2.65 (m, 1H), 1.77-1.79 (m, 2H), 1.38 (s, 9H)and 1.13-1.19 (m, 3H). LCMS: 324.12 (M+H)⁺, 85.32%. Yield: 78%.

tert-Butyl 4-((2-amino-4-fluorobenzyl)amino)piperidine-1-carboxylate(32.4b)

¹H-NMR (400 MHz, DMSO-d₆): δ 6.95-6.98 (m, 1H), 6.35-6.38 (m, 1H),6.20-6.25 (m, 1H), 5.52 (br s, 2H), 3.78-3.81 (m, 2H), 3.60 (s, 2H),2.66-2.83 (m, 3H), 1.77-1.80 (m, 2H), 1.38 (s, 9H) and 1.13-1.20 (m,3H). LCMS: 324.22 (M+H)⁺, 84.74%. Yield: 91%.

General Procedure for the Preparation of 32.5(a-b):

To an ice-cold solution of compound 32.4 (a-b) (1.0 eq) in THF was addedEt₃N (2.0 eq) and triphosgene (1.5 eq). The resulting reaction mixturewas stirred at RT for 4 h. After completion of the reaction (TLCmonitoring), the solvent was evaporated and the residue was diluted withwater and extracted with ethyl acetate (3 times). The combined organicswere washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude was purified over silica gel (100-200 M, 30-40%EtOAc-hexane) to get the desired product 32.5 (a-b).

tert-Butyl4-(5-fluoro-2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carboxylate(32.5a)

¹H-NMR (400 MHz, CDCl₃): δ 7.62 (br s, 1H), 7.09-7.20 (m, 1H), 6.63 (t,J=8.8 Hz, 1H), 6.45 (d, J=7.6 Hz, 1H), 4.50-4.56 (m, 1H), 4.37 (s, 2H),4.11-4.12 (m, 2H), 2.83-2.88 (m, 2H), 1.71-1.77 (m, 4H) and 1.47 (s,9H). LCMS: 350.35 (M+H)⁺, 96.92%. Yield: 85%.

tert-Butyl4-(7-fluoro-2-oxo-1,4-dihydroquinazolin-3(2H)-yl)piperidine-1-carboxylate(32.5b)

¹H-NMR (400 MHz, CDCl₃): δ 7.63 (br s, 1H), 6.96-7.00 (m, 1H), 6.61-6.65(m, 1H), 6.43-6.46 (m, 1H), 4.48-4.56 (m, 1H), 4.27-4.33 (m, 4H),2.83-2.88 (m, 2H), 1.69-1.72 (m, 4H) and 1.47 (s, 9H). LCMS: 350.39(M+H)⁺, 92.96%. Yield: 55%.

General Procedure for the Preparation of 32.6(a-b):

An ice-cold solution of compound 32.5(a-b) in dioxane-HCl (˜4N) wasstirred at RT for 2 h. After completion of the reaction (TLCmonitoring), the reaction mass was dried under reduced pressure. Thecrude was triturated with diethyl ether to get desired product 32.6(a-b)as an off-white solid.

5-Fluoro-3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-oneHydrochloride (32.6a)

Intermediate-24: ¹H-NMR (400 MHz, DMSO-d₆): δ 9.54 (br s, 1H), 8.87 (brs, 1H), 8.61 (br s, 1H), 7.14-7.18 (m, 1H), 6.70-6.75 (m, 1H), 6.59-6.61(m, 1H), 4.35-4.43 (m, 3H), 3.32-3.35 (m, 2H), 3.00-3.03 (m, 2H),2.05-2.14 (m, 2H) and 1.72-1.75 (m, 2H). LCMS: 250.23 (M+H)⁺, 98.92%.Yield: 97%.

7-Fluoro-3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-oneHydrochloride (32.6b)

Intermediate-25: ¹H-NMR (400 MHz, DMSO-d₆): δ 9.46 (br s, 1H), 8.94 (brs, 1H), 8.81 (br s, 1H), 7.16-7.22 (m, 1H), 6.68-6.71 (m, 1H), 6.55-6.58(m, 1H), 4.32-4.38 (m, 1H), 4.27 (s, 2H), 3.83-3.85 (m, 2H), 3.32-3.38(m, 2H), 2.01-2.07 (m, 2H) and 1.70-1.73 (m, 2H). LCMS: 250.10 (M+H)⁺,96.20%. Yield: 98%.

Preparation of 4-ethoxy-3,4-dioxo-1-(pyridin-3-yl)but-1-en-1-olateLithium Salt (33.3) (General Method O)

A solution of 3-acetyl pyridine 33.1 (20 g, 165.09 mmol) in di-ethylether (250 mL) was cooled to −78° C. followed by addition of LiHMDS (1.0M in THF, 181.60 mL, 181.60 mmol). The resulting reaction mixture wasstirred at −78° C. for 45 min followed by drop wise addition of diethyloxalate 33.2 (27.03 mL, 198.10 mmol) in about 20 min. The reactionmixture was then left to stir at room temperature for 16 h. Aftercompletion of the reaction (TLC and MS monitoring), the solution wasthen cooled to 0° C. and diluted with added diethyl ether (250 mL) andstirred for 30.0 min. The resulting precipitate was filtered to get thedesired product 33.3 as an off-white solid (30 g, Yield: 82%), which wascarried forward to the next step without purification. ¹H-NMR (400 MHz,DMSO-d₆): δ 8.95 (s, 1H), 8.61 (d, J=4.0 Hz, 1H), 8.14 (m, 1H), 7.44 (m,1H), 6.40 (m, 1H), 4.12 (q, J=7.20 Hz, 2H) and 1.21 (t, J=7.2 Hz, 3H).MS: 221.95 (M+H)⁺.

Preparation of ethyl5-(pyridin-3-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carboxylate(33.5)

To an ice-cold solution of4-ethoxy-3,4-dioxo-1-(pyridin-3-yl)but-1-en-1-olate lithium salt 33.3(10.0 g, 45.23 mmol) in IPA (50 mL) was added(3,4,5-trifluorophenyl)hydrazine hydrochloride 33.4 (10.77 g, 54.28mmol) and TFA (6.9 mL, 90.46 mmol). The resulting reaction mixture waswarmed to room temperature and then stirred at 90° C. for 4 h. Aftercompletion of the reaction (TLC monitoring), the solvent was evaporatedand the residue was diluted with water and extracted with ethyl acetate(3 times). The combined organics were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated. The crude waspurified over silica gel (100-200 M, 10-15% EtOAc-hexane) to get thedesired product 33.5 (5.50 g, 35%). ¹H-NMR (400 MHz, CDCl₃): δ 8.68 (m,1H), 8.61 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.42 (m, 1H), 7.14 (s, 1H),7.03 (m, 2H), 4.48 (q, J=7.2 Hz, 2H) and 1.41 (t, J=7.2 Hz, 3H). MS:348.15 (M+H)⁺.

Preparation of5-(pyridin-3-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carboxylic Acid(33.6)

To an ice-cold solution of ethyl5-(pyridin-3-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carboxylate33.5 (5.50 g, 15.82 mmol) in EtOH (40 mL) was added drop wise an aqueoussolution of sodium hydroxide (1.26 g, 31.64 mmol). The resultingsolution was stirred at room temperature for 2 h. After completion ofthe reaction (TLC monitoring), the solvent was evaporated, added H₂O tothe residue followed by extraction with EtOAc (2×100 mL). The organiclayer was discarded and the pH of the aqueous layer was adjusted to ˜4by adding 1N HCl. The resulting precipitate was filtered and dried undervacuum to get the desired product 33.6 (3.0 g, 59%) as a white solid.¹H-NMR (400 MHz, DMSO-d₆): δ 13.13 (br s, 1H), 8.59 (s, 2H), 7.65 (d,J=8.4 Hz, 1H), 7.52 (m, 2H), 7.41 (m, 1H) and 7.25 (s, 1H). LCMS: 320.14(M+H)⁺, 95.20%.

General Procedure for the Preparation of Final Compounds 33.7

General Method-P:

To an ice-cold solution of carboxylic acid 33.6 (125-150 mg), in DMF(2.0 mL) was added DIPEA (2.5 eq) and HATU (1.50 eq). The resultingmixture was stirred under nitrogen atmosphere at 0° C. for 15 minfollowed by addition of respective amines (1.20 eq). The reactionmixture was then stirred at room temperature for 16 h. After thecompletion of the reaction (TLC monitoring), the solution was dilutedwith ice-cold water (30 mL) followed by extraction with EtOAc (3×50 mL).The combined organics were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The cruderesidue was purified via prep-HPLC.

The yields and analytical data of the compounds are set forth in Table6.10.

TABLE 6.10 Tabulated data of the final compounds including theindividual yields Com- Amine pound intermediate Yield ¹H-NMR data(DMSO-d₆, 400 ID Structure used (%) LCMS MHz), unless otherwisespecified 267

Intermediate- 5 23 560.13 (M − H)⁺, 99.72% δ 11.25 (br s, 1H), 8.59-8.60(m, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.61- 7.64 (m, 1H), 7.49-7.53 (m,2H), 7.41-7.43 (m, 1H), 7.36-7.38 (m, 1H), 7.14 (s, 1H), 4.77-4.80 (m,1H), 4.70-4.73 (m, 1H), 4.49-4.55 (m, 1H), 3.30-3.32 (m, 1H), 2.88- 2.94(m, 1H), 2.26-2.29 (m, 2H) and 1.77-1.80 (m, 2H) 268

Intermediate- 11 33 581.20 (M + H)⁺ 97.77% δ 11.27 (br s, 1H), 8.59-8.60(m, 2H), 7.68-7.61 (m, 1H), 7.52-7.55 (m, 2H), 7.42-7.45 (m, 1H), 7.22(s, 1H), 7.01-7.06 (m, 1H), 6.77- 6.80 (m, 1H), 5.32-5.36 (m, 1H),4.84-4.88 (m, 1H), 4.36-4.43 (m, 1H), 3.36-3.40 (m, 1H), 2.55-2.58 (m,1H), 3.11-2.14 (m, 1H), 2.00- 2.03 (m, 1H) and 1.84-1.89 (m, 4H).

General Procedure for the Preparation of Compounds 34.2 (a-f):

General Method Q:

To an ice-cold solution of4-ethoxy-2-methyl-3,4-dioxo-1-(pyridin-3-yl)but-1-en-1-olate lithiumsalt 34.1 (3.0 g, 13.21 mmol) in IPA was added the respective hydrazinehydrochloride (1.2 eq) and TFA (2.0 eq). The resulting reaction mixturewas warmed up to room temperature and then stirred at 90° C. for 4-5 h.After completion of the reaction (TLC monitoring), the solvent wasevaporated and the residue was diluted with water and extracted withethyl acetate (3 times). The combined organics were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated. Thecrude was purified over silica gel (100-200 M, 10-15% EtOAc-hexane) toget the desired product 34.2 (a-f).

Ethyl1-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(34.2a)

¹H-NMR (400 MHz, CDCl₃): δ 8.59-8.66 (m, 1H), 7.77-7.78 (m, 1H), 7.56(d, J=8.4 Hz, 1H), 7.38-7.41 (m, 2H), 7.23-7.25 (m, 1H), 7.21 (s, 1H),7.07-7.10 (m, 1H), 4.48 (q, J=7.2 Hz, 2H) and 1.38 (t, J=7.6 Hz, 3H).MS: 380.22 (M+H)⁺. Yield: 35%.

Ethyl1-(4-cyano-3-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(34.2b)

¹H-NMR (400 MHz, CDCl₃): δ 8.81-8.84 (m, 1H), 8.62 (s, 1H), 7.91 (s,1H), 7.81-7.83 (m, 1H), 7.60-7.62 (m, 1H), 7.51-7.53 (m, 1H), 7.43-7.46(m, 1H), 7.17 (s, 1H), 4.45 (q, J=7.2 Hz, 2H) and 1.44 (t, J=7.2 Hz,3H). MS: 387.25 (M+H)⁺. Yield: 47%.

Ethyl1-(3,4-bis(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(34.2c)

¹H-NMR (400 MHz, CDCl₃): δ 8.70-8.71 (m, 1H), 8.64 (s, 1H), 7.93 (s,1H), 7.84 (d, J=8.4 Hz, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.55 (d, J=8.4 Hz,1H), 7.45-7.49 (m, 1H), 7.18 (s, 1H), 4.39 (q, J=7.2 Hz, 2H) and 1.42(t, J=7.2 Hz, 3H). LCMS: 430.21 (M+H)⁺, 90.74%. Yield: 51%.

Ethyl1-(4-fluoro-3-methyl-5-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(34.2d)

¹H-NMR (400 MHz, CDCl₃): δ 8.54-8.64 (m, 2H), 7.55-7.57 (m, 1H),7.38-7.45 (m, 3H), 7.13 (s, 1H), 4.44 (q, J=7.2 Hz, 2H), 2.30 (s, 3H)and 1.33 (t, J=7.2 Hz, 3H). LCMS: 394.23 (M+H)⁺, 90.43%. Yield: 70%.

Ethyl1-(4-chloro-3-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(34.2e)

MS: 396.20 (M+H)⁺. Yield: 48%.

Ethyl1-(2,4-difluoro-3-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(34.2f)

¹H-NMR (400 MHz, CDCl₃): δ 8.71-8.77 (m, 1H), 7.84-7.93 (m, 3H),7.61-7.65 (m, 1H), 7.22-7.25 (m, 1H), 7.19 (s, 1H), 4.47 (q, J=6.8 Hz,2H) and 1.43 (t, J=7.2 Hz, 3H). MS: 398.34 (M+H)⁺. Yield: 15%.

General Procedure for the Preparation of Compounds 34.3 (a-f)

General Method R:

To an ice-cold solution of compound 34.3 (a-f) (0.80-1.5 g, 1.0 eq) inEtOH was added dropwise an aqueous solution of sodium hydroxide (3.0eq). The resulting solution was stirred at room temperature for 2-3 h.After completion of the reaction (TLC monitoring), the solvent wasevaporated, added H₂O to the residue followed by extraction with EtOAc(2×100 mL). The organic layer was discarded and the pH of the aqueouslayer was adjusted to ˜4 by adding 1N HCl. The resulting precipitate wasfiltered and dried under vacuum to get the desired product 34.3(a-f) asa white solid.

1-(4-Fluoro-3-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (34.3a)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.15 (br s, 1H), 8.57-8.58 (m, 2H),7.84-7.86 (m, 1H), 7.60-7.69 (m, 3H), 7.40-7.45 (m, 1H) and 7.24 (s,1H). LCMS: 352.24 (M+H)⁺, 95.84%. Yield: 73%.

1-(4-Cyano-3-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (34.3b)

LCMS: 359.26 (M+H)+, 99.29%. Yield: 96%.

1-(3,4-Bis(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (34.3c)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.28 (br s, 1H), 8.59-8.62 (m, 2H),8.12-8.14 (m, 1H), 8.00 (s, 1H), 7.75-7.83 (m, 2H), 7.46-7.47 (m, 1H)and 7.29 (s, 1H). LCMS: 402.18 (M+H)⁺, 95.09%. Yield: 70%.

1-(4-Fluoro-3-methyl-5-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (34.3d)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.12 (br s, 1H), 8.53-8.57 (m, 2H),7.74-7.75 (m, 1H), 7.66-7.68 (m, 1H), 7.56 (s, 1H), 7.40-7.43 (m, 1H),7.24 (s, 1H) and 2.29 (s, 3H). LCMS: 366.22 (M+H)⁺, 91.97%. Yield: 90%.

1-(4-Chloro-3-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (34.3e)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.22 (br s, 1H), 8.57-8.60 (m, 2H), 7.87(s, 1H), 7.80-7.82 (m, 1H), 7.70-7.72 (m, 1H), 7.60-7.62 (m, 1H),7.41-7.44 (m, 1H) and 7.25 (s, 1H). LCMS: 368.15 (M+H)⁺, 97.03%. Yield:58%.

1-(2,4-Difluoro-3-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (34.3f)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.20 (br s, 1H), 8.54-8.59 (m, 2H),8.12-8.15 (m, 1H), 7.60-7.68 (m, 2H), 7.46-7.48 (m, 1H) and 7.32 (s,1H). MS: 370.11 (M+H)⁺. Yield: 42%.

General Procedure for the Preparation of Final Compounds:

The final compounds were prepared following the general method P (Scheme10).

The yields and analytical data of the final compounds are set forth inTable 6.11.

TABLE 6.11 Tabulated data of the final compounds including theindividual yields Com- Amine ¹H-NMR data (DMSO-d₆, 400 poundintermediate Yield MHz), unless otherwise ID Structure used (%) LCMSspecified 269

Intermediate- 1 36 581.09 (M − H)⁺, 99.77% δ 8.81 (s, 1H), 8.57-8.59 (m,2H), 7.80-7.82 (m, 1H), 7.67-7.70 (m, 2H), 7.58-7.62 (m, 1H), 7.41-7.44(m, 1H), 7.09-7.13 (m, 3H), 6.84- 6.87 (m, 2H), 4.59 (s, 2H), 4.45 (s,2H), 3.83-3.88 (m, 1H), 3.50- 3.56 (m, 1H), 2.23-2.32 (m, 2H) and1.72-1.82 (m, 2H) 270

Intermediate- 4 26 576.23 (M + H)⁺ 98.97% δ 11.24 (br s, 1H), 8.59-8.60(m, 2H), 7.82-7.83 (m, 2H), 7.68-7.76 (m, 2H), 7.60-7.65 (m, 1H), 7.41-7.44 (m, 2H), 7.14 (s, 1H), 7.10 (d, J = 8.0 Hz, 1H), 4.71-4.74 (m, 2H),4.51-4.57 (m, 1H), 3.28-3.32 (m, 1H), 2.89-2.95 (m, 1H), 2.29- 2.35 (m,2H) and 1.76-1.82 (m, 2H) 271

Intermediate- 3 45 587.17 (M + H)⁺ 99.93% δ 11.26 (br s, 1H), 8.57-8.59(m, 2H), 7.82-7.83 (m, 1H), 7.69-7.73 (m, 2H), 7.60-7.64 (m, 1H), 7.41-7.44 (m, 1H), 7.14 (s, 1H), 7.00- 7.05 (m, 1H), 6.77-6.80 (m, 1H),4.78-4.81 (m, 1H), 4.68-4.70 (m, 2H), 3.30-3.32 (m, 1H), 2.92-2.96 (m,1H), 2.07-2.14 (m, 2H) and 1.84-1.87 (m, 2H) 272

Intermediate- 12 13 588.18 (M + H)⁺ 99.73% δ 10.54 (br s, 1H), 8.57-8.59(m, 2H), 7.81-7.82 (m, 1H), 7.74-7.76 (m, 1H), 7.68-7.70 (m, 1H), 7.60-7.64 (m, 1H), 7.35-7.44 (m, 2H), 7.15 (s, 1H), 6.73-7.74 (m, 1H),4.57-4.68 (m, 2H), 3.52-3.58 (m, 1H), 3.17-3.19 (m, 1H) and 2.16- 2.22(m, 4H). 273

Intermediate- 13 13 588.14 (M + H)⁺ 99.88% δ 10.44 (br s, 1H), 8.57-8.60(m, 2H), 7.80-7.82 (m, 1H), 7.56-7.80 (m, 4H), 7.41-7.44 (m, 1H), 7.14(s, 1H), 6.85-6.89 (m, 1H), 4.57- 4.66 (m, 2H), 3.48-3.54 (m, 1H),3.09-3.14 (m, 1H) and 2.00-2.09 (m, 4H). 274

Intermediate- 14 27 620.15 (M + H)⁺ 99.87% δ 10.71 (br s, 1H), 8.58-8.60(m, 2H), 7.81-7.82 (m, 1H), 7.60-7.65 (m, 5H), 7.41-7.44 (m, 1H), 7.14(s, 1H), 7.06-7.08 (d, J = 2.0 Hz, 1H), 4.59-4.67 (m, 2H), 3.50-3.56 (m,1H), 3.11-3.17 (m, 1H) and 2.03-2.10 (m, 4H). 275

Intermediate- 15 23 620.18 (M + H)⁺ 99.42% δ 10.70 (br s, 1H), 8.58-8.60(m, 2H), 7.80-7.82 (m, 1H), 7.74-7.77 (m, 1H), 7.67-7.80 (m, 1H), 7.60-7.65 (m, 2H), 7.41-7.44 (m, 1H), 7.36-7.38 (m, 1H), 7.17-7.19 (m, 1H),7.15 (s, 1H), 4.59-4.68 (m, 2H), 3.52-3.58 (m, 1H), 3.14-3.19 (m, 1H)and 2.07-2.14 (m, 4H). 276

Intermediate- 16 31 638.19 (M + H)⁺ 99.04% δ 10.59 (br s, 1H), 8.58-8.59(m, 2H), 7.81-7.82 (m, 1H), 7.73-7.76 (m, 1H), 7.60-7.70 (m, 3H), 7.41-7.44 (m, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.14 (s, 1H), 4.59-4.69 (m, 2H),3.49-3.56 (m, 1H), 3.10-3.16 (m, 1H) and 2.05-2.13 (m, 4H). 277

Intermediate- 17 14 604.09 (M + H)⁺ 97.81% δ 10.47 (br s, 1H), 8.58-8.59(m, 2H), 7.81-7.82 (m, 1H), 7.73-7.75 (m, 1H), 7.55-7.68 (m, 3H), 7.41-7.44 (m, 1H), 7.14 (s, 1H), 7.01 (d, J = 6.4 Hz, 1H), 4.57-4.66 (m, 2H),3.48-3.55 (m, 1H), 3.13-3.16 (m, 1H) and 2.01-2.15 (m, 4H). 278

Intermediate- 18 7 570.21 (M + H)⁺ 97.52% δ 10.45 (br s, 1H), 8.57-8.59(m, 2H), 7.80-7.81 (m, 1H), 7.60-7.79 (m, 3H), 7.32-7.44 (m, 2H), 7.14(s, 1H), 6.82-6.87 (m, 1H), 6.68- 6.71 (m, 1H), 4.57-4.64 (m, 2H),3.50-3.56 (m, 1H), 3.12-3.17 (m, 1H) and 2.01-2.08 (m, 4H) 279

Intermediate- 19 4 570.25 (M + H)⁺ 97.65% δ 10.56 (br s, 1H), 8.57-8.59(m, 2H), 7.80-7.83 (m, 1H), 7.60-7.77 (m, 3H), 7.41-7.44 (m, 1H), 7.27-7.33 (m, 1H), 7.15 (s, 1H), 6.83- 6.88 (m, 1H), 6.74 (d, J = 8.0 Hz,1H), 4.55-4.67 (m, 2H), 3.52-3.58 (m, 1H), 3.13-3.18 (m, 1H) and2.12-2.27 (m, 4H) 280

33 586.13 (M + H)⁺ 99.83% δ 10.44 (br s, 1H), 8.58-8.60 (m, 2H),7.80-7.81 (m, 1H), 7.68-7.76 (m, 2H), 7.60-7.64 (m, 1H), 7.47- 7.48 (m,1H), 7.41-7.44 (m, 1H), 7.31-7.34 (m, 1H), 7.14 (s, 1H), 6.90 (d, J =8.4 Hz, 1H), 4.57-4.63 (m, 2H), 3.49-3.55 (m, 1H), 3.13- 3.17 (m, 1H)and 2.00-2.16 (m, 4H) 281

34 553.15 (M + H)⁺ 99.23% δ 10.92 (br s, 1H), 8.57-8.60 (m, 2H),8.20-8.21 (m, 1H), 7.60-7.81 (m, 5H), 7.41-7.44 (m, 1H), 7.14 (s, 1H),7.06-7.09 (m, 1H), 4.59- 4.67 (m, 2H), 3.50-3.57 (m, 1H), 3.13-3.18 (m,1H) and 2.04-2.13 (m, 4H) 282

Intermediate- 20 10 570.18 (M + H)⁺ 99.67% δ 10.36 (br s, 1H), 8.58-8.59(m, 2H), 7.80-7.82 (m, 1H), 7.60-7.77 (m, 3H), 7.41-7.44 (m, 1H), 7.30-7.33 (m, 1H), 7.15 (s, 1H), 7.10- 7.13 (m, 1H), 6.89-6.93 (m, 1H),4.57-4.65 (m, 2H), 3.49-3.55 (m, 1H), 3.10-3.17 (m, 1H) and 2.00- 2.17(m, 4H) 283

Intermediate- 2 19 631.17 (M − H)⁺, 97.58% δ 8.83 (s, 1H), 8.57-8.59 (m,2H), 7.79-7.81 (m, 1H), 7.67-7.73 (m, 2H), 7.57-7.62 (m, 1H), 7.41-7.44(m, 1H), 6.81-7.20 (m, 6H), 4.60 (s, 2H), 4.48 (s, 2H), 3.84-3.90 (m,1H), 3.50-3.56 (m, 1H), 2.33- 2.37 (m, 2H) and 1.72-1.81 (m, 2H) 284

Intermediate- 3 48 594.16 (M + H)⁺ 98.92% δ 11.25 (br s, 1H), 8.63 (s,2H), 8.23 (d, J = 8.4 Hz, 1H), 7.94 (s, 1H), 7.75-7.82 (m, 2H), 7.44-7.47 (m, 1H), 7.18 (s, 1H), 7.00- 7.07 (m, 1H), 6.77-6.80 (m, 1H),4.68-4.70 (m, 3H), 3.36-3.39 (m, 1H), 2.94-3.0 (m, 1H), 2.12-2.16 (m,2H) and 1.84-1.93 (m, 2H) 285

Intermediate- 3 51 637.21 (M + H)⁺ 99.79% δ 11.17 (br s, 1H), 8.62 (s,2H), 8.11 (d, J = 8.4 Hz, 1H), 7.96 (s, 1H), 7.77-7.85 (m, 2H),7.44-7.48 (m, 1H), 7.17 (s, 1H), 7.00-7.07 (m, 1H), 6.77-6.80 (m, 1H),4.68- 4.74 (m, 3H), 3.36-3.39 (m, 1H), 2.95-3.01 (m, 1H), 2.07-2.15 (m,2H) and 1.85-1.93 (m, 2H) 286

Intermediate- 3 17 601.21 (M + H)⁺ 99.44% δ 11.14 (br s, 1H), 8.58 (s,2H), 7.74-7.75 (m, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H),7.40-7.43 (m, 1H), 7.13 (s, 1H), 6.99-7.08 (m, 1H), 6.77-6.79 (m, 1H),4.77- 4.80 (m, 1H), 4.56-4.70 (m, 2H), 3.33-3.36 (m, 1H), 2.92-2.98 (m,1H), 2.28 (s, 3H), 2.08-2.14 (m, 2H) and 1.84-1.92 (m, 2H) 287

Intermediate- 22 30 602.15 (M + H)⁺ 98.84% δ 8.57-8.59 (m, 2H),7.81-7.82 (m, 1H), 7.74-7.76 (m, 1H), 7.65- 7.68 (m, 1H), 7.60-7.62 (m,1H), 7.47-7.49 (m, 1H), 7.41-7.44 (m, 1H), 7.15 (s, 1H), 6.98-.700 (m,1H), 4.67-4.71 (m, 1H), 4.57-4.60 (m, 1H), 3.51-3.55 (m, 1H), 3.30 (s,3H), 3.16-3.19 (m, 1H) and 2.22-2.24 (m, 4H). 288

Intermediate- 23 22 634.19 (M + H)⁺ 99.86% δ 8.58-8.60 (m, 2H),7.81-7.82 (m, 1H), 7.59-7.68 (m, 5H), 7.41- 7.44 (m, 1H), 7.30 (d, J =8.4 Hz, 1H), 7.14 (s, 1H), 4.60-4.71 (m, 2H), 3.51-3.57 (m, 1H), 3.31(s, 3H), 3.11-3.17 (m, 1H) and 2.06- 2.16 (m, 4H). 289

Intermediate- 24 6 583.25 (M + H)⁺ 99.25% δ 9.47 (s, 1H), 8.57-8.59 (m,2H), 7.80-7.82 (m, 1H), 7.60-7.76 (m, 3H), 7.41-7.44 (m, 1H), 7.12-7.18(m, 1H), 7.11 (s, 1H), 6.67 (t, J = 8.8 Hz, 1H), 6.58 (d, J = 8.0 Hz,1H), 4.65-4.68 (m, 2H), 4.43-4.49 (m, 1H), 4.37 (s, 2H), 3.16-3.21 (m,1H), 2.83-2.89 (m, 1H), 1.81- 1.86 (m, 2H) and 1.64-1.70 (m, 2H). 290

Intermediate- 25 20 583.25 (M + H)⁺ 98.71% δ 9.36 (s, 1H), 8.57-8.59 (m,2H), 7.80-7.82 (m, 1H), 7.60-7.75 (m, 3H), 7.41-7.44 (m, 1H), 7.12-7.15(m, 1H), 7.10 (s, 1H), 6.65 (t, J = 8.4 Hz, 1H), 6.53-6.56 (m, 1H),4.65-4.68 (m, 2H), 4.45-4.49 (m, 1H), 4.27 (s, 2H), 3.22-3.24 (m, 1H),2.82-2.86 (m, 1H), and 1.62- 1.80 (m, 4H). 291

Intermediate- 7 7 603.20 (M + H)⁺ 99.62% δ 13.25 (br s, 1H), 8.58 (s,2H), 7.81-7.83 (m, 1H), 7.70-7.75 (m, 2H), 7.59-7.64 (m, 1H), 7.41-7.44(m, 1H), 7.24-7.31 (m, 1H), 7.17 (s, 1H), 6.99-7.02 (m, 1H), 5.63 (s,1H), 4.84-4.87 (m, 1H), 4.71- 4.74 (m, 1H), 3.39-3.42 (m, 1H), 2.97-3.03(m, 1H), 2.07-2.11 (m, 2H) and 1.86-1.90 (m, 2H 292

Intermediate- 21 11 632.14 (M − H)⁺ 99.65% δ 10.71 (br s, 1H), 8.58-8.60(m, 2H), 6.60-7.83 (m, 6H), 7.42-7.44 (m, 1H), 7.14 (s, 1H), 7.05-7.09(m, 1H), 4.84-4.95 (m, 1H), 4.53- 4.60 (m, 1H), 3.57-3.60 (m, 1H),2.32-2.34 (m, 1H), 2.20-2.24 (m, 1H), 2.13-2.15 (m, 2H), and 1.50 (d, J= 6.4 Hz, 3H) 293

Intermediate- 9 23 601.28 (M + H)⁺ 99.91% δ 10.27 (br s, 1H), 8.59-8.60(m, 2H), 7.81-7.82 (m, 1H), 7.70-7.76 (m, 2H), 7.59-7.64 (m, 1H), 7.42-7.45 (m, 1H), 7.15 (s, 1H), 7.01- 7.08 (m, 1H), 6.78-6.81 (m, 1H),4.38-4.53 (m, 3H), 3.56-3.58 (m, 1H), 2.17-2.32 (m, 2H), 1.98- 2.01 (m,2H) and 1.30 (d, J = 6.0 Hz, 3H) 294

Intermediate- 10 13 617.23 (M + H)⁺ 97.62% δ 13.24 (br s, 1H), 8.57-8.59(m, 2H), 7.81-7.84 (m, 1H), 7.68-7.77 (m, 2H), 7.59-7.64 (m, 1H), 7.41-7.44 (m, 1H), 7.26-7.31 (m, 1H), 7.17 (s, 1H), 7.00-7.03 (m, 1H), 5.47(s, 1H), 4.48-4.53 (m, 2H), 3.59-3.62 (m, 1H), 2.19-2.32 (m, 2H),1.89-2.01 (m, 2H) and 1.32 (d, J = 6.0 Hz, 3H) 295

Intermediate- 3 22 601.07 (M − H)⁺ 99.74% δ 11.22 (br s, 1H), 8.59-8.61(m, 2H), 7.80-7.84 (m, 2H), 7.72-7.74 (m, 1H), 7.63-7.66 (m, 1H), 7.42-7.45 (m, 1H), 7.14 (s, 1H), 7.00- 7.07 (m, 1H), 6.77-6.80 (m, 1H),4.67-4.78 (m, 3H), 3.27-3.30 (m, 1H), 2.93-2.99 (m, 1H), 2.11-2.24 (m,2H) and 1.84-1.92 (m, 2H) 296

Intermediate- 1 11 599.23 (M + H)⁺, 96.98% δ 8.80 (s, 1H), 8.58-8.61 (m,2H), 7.78-7.82 (m, 2H), 7.70-7.72 (m, 1H), 7.58-7.61 (m, 1H), 7.42-7.45(m, 1H), 7.15 (s, 1H), 7.07-7.13 (m, 2H), 6.84-6.88 (m, 2H), 4.59 (s,2H), 4.42-4.45 (m, 2H), 3.83- 3.89 (m, 1H), 3.50-3.56 (m, 1H), 2.19-2.29(m, 2H) and 1.73-1.83 (m, 2H) 297

Intermediate- 6 19 605.21 (M + H)⁺ 98.97% δ 11.22 (br s, 1H), 8.58-8.59(m, 2H), 7.81-7.83 (m, 1H), 7.68-7.76 (m, 2H), 7.59-7.64 (m, 1H), 7.40-7.44 (m, 1H), 7.13 (s, 1H), 6.96- 7.00 (m, 1H), 4.77-4.81 (m, 1H),4.60-4.67 (m, 2H), 3.31-3.32 (m, 1H), 2.92-2.97 (m, 1H), 2.08-2.14 (m,2H) and 1.83-1.91 (m, 2H) 298

Intermediate- 8 7 621.19 (M + H)⁺ 96.88% δ 13.40 (br s, 1H), 8.58-8.59(m, 2H), 7.82-7.84 (m, 1H), 7.69-7.76 (m, 2H), 7.59-7.64 (m, 1H), 7.41-7.44 (m, 1H), 7.11-7.15 (m, 2H), 5.62-5.64 (m, 1H), 4.84-4.87 (m, 1H),4.71-4.74 (m, 1H), 3.39- 3.42 (m, 1H), 2.97-3.03 (m, 1H), 2.03-2.07 (m,2H) and 1.85-1.89 (m, 2H) 299

Intermediate- 3 19 605.35 (M + H)⁺ 99.74% δ 11.20 (br s, 1H), 8.58-8.59(m, 2H), 8.12-8.18 (m, 1H), 7.69-7.72 (m, 1H), 7.57-7.62 (m, 1H), 7.40-7.43 (m, 1H), 7.21 (s, 1H), 6.99- 7.06 (m, 1H), 6.76-6.79 (m, 1H),4.62-4.75 (m, 3H), 3.30-3.32 (m, 1H), 2.92-2.98 (m, 1H), 2.07-2.16 (m,2H) and 1.83-1.92 (m, 2H) 300

Intermediate- 1 21 601.38 (M + H)⁺ 98.66% δ 8.79 (br s, 1H), 8.59 (d, J= 2.80 Hz, 2H), 8.08-8.14 (m, 1H), 7.67- 7.69 (m, 1H), 7.56-7.61 (m,1H), 7.40-7.43 (m, 1H), 7.22 (s, 1H), 7.06-7.10 (m, 2H), 6.83-6.87 (m,2H), 4.58 (s, 2H), 4.43 (d, J = 12.40 Hz, 2H), 3.83-3.89 (m, 1H),3.51-3.57 (m, 1H), 2.19-2.31 (m, 2H) and 1.72-1.83 (m, 2H)

General Procedure for the Preparation of Compounds 35.2(a-b) (GeneralMethod P):

To an ice-cold solution of 2-methoxyisonicotinic acid 35.1a or6-methoxynicotinic acid 35.1b (1.0 eq) in DMF was added DIPEA (1.5 eq)and HATU (1.50 eq). The resulting mixture was stirred under nitrogenatmosphere at 0° C. for 15 min followed by addition ofN,O-dimethylhydroxylamine hydrochloride (1.1 eq). The reaction mixturewas then stirred at room temperature for 16 h. After the completion ofthe reaction (TLC monitoring), the solution was diluted with ice-coldwater followed by extraction with EtOAc (3 times). The combined organicswere washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude was purified by silicagel (100-200 M), elution with 2-3% MeOH/DCM to get desired product35.2(a-b) as a viscous liquid.

N,2-Dimethoxy-N-methylisonicotinamide (35.2a)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.24 (d, J=5.2 Hz, 1H), 7.07 (d, J=4.8 Hz,1H), 6.91 (s, 1H), 3.89 (s, 3H), 3.24 (s, 3H) and 2.68 (s, 3H). MS:197.09 (M+H)⁺. Yield: 96%.

N,6-Dimethoxy-N-methylnicotinamide (35.2b)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.76 (d, J=4.0 Hz, 1H), 7.50-7.53 (m, 1H),6.86-6.91 (m, 1H), 3.90 (s, 3H), 3.26 (s, 3H) and 2.72 (s, 3H). MS:197.19 (M+H)⁺. Yield: 42%.

General Procedure for the Preparation of Compounds 35.3(a-b) (GeneralMethod S):

A solution of 35.2 (a-b) (1.0 eq) in THF was cooled to −78° C. followedby addition of ethyl magnesium bromide (1.5 eq, 2 M in THF) slowly underN₂ atmosphere. The reaction mixture was then left to stir at roomtemperature for 16 h. After completion of the reaction (TLC and MSmonitoring), the solution was then cooled to 0° C. and diluted withsaturated solution of NH₄Cl and extracted with EtOAc (3 times). Thecombined organics were washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated. The crude was purified over silicagel (100-200 M, 10-15% EtOAc-hexane) to get the desired product35.3(a-b) as a viscous liquid.

1-(2-Methoxypyridin-4-yl)propan-1-one (35.3a)

¹H-NMR (400 MHz, CDCl₃): δ 8.29 (d, J=5.2 Hz, 1H), 7.30 (d, J=4.4 Hz,1H), 7.18 (s, 1H), 3.97 (s, 3H), 2.93 (q, J=7.2 Hz, 2H) and 1.19 (t,J=7.2 Hz, 3H). LCMS: 165.98 (M+H)⁺, 97.50%. Yield: 42%.

1-(6-Methoxypyridin-3-yl)propan-1-one (35.3b)

¹H-NMR (400 MHz, CDCl₃): δ 8.80 (s, 1H), 8.29 (dd, J=2.0 & 8.8 Hz, 1H),6.78 (d, J=8.8 Hz, 1H), 4.10 (s, 3H), 2.92 (q, J=7.2 Hz, 2H) and 1.21(t, J=7.2 Hz, 3H). LCMS: 166.25 (M+H)⁺, 96.69%. Yield: 75%.

General Procedure for the Preparation of Compounds 35.4(a-b):

These compounds were prepared following the general method O (Scheme33).

4-Ethoxy-1-(2-methoxypyridin-4-yl)-2-methyl-3,4-dioxobut-1-en-1-olateLithium Salt (35.4a)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.33-8.36 (m, 1H), 7.36-7.40 (m, 1H),7.20-7.23 (m, 1H), 4.34 (q, J=7.20 Hz, 2H), 3.95 (s, 3H), 1.63 (s, 3H)and 1.09 (t, J=6.8 Hz, 3H). MS: 266.28 (M+H)⁺. Yield: 90%.

4-Ethoxy-1-(6-methoxypyridin-3-yl)-2-methyl-3,4-dioxobut-1-en-1-olate(35.4b)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.74 (s, 1H), 7.56-7.58 (m, 1H), 6.91-6.93(m, 1H), 4.29 (q, J=7.20 Hz, 2H), 3.97 (s, 3H), 1.65 (s, 3H) and 1.09(t, J=7.6 Hz, 3H). MS: 266.04 (M+H)⁺. Yield: 72%.

General Procedure for the Preparation of Compounds 35.5 (a-b):

These compounds were prepared following the general method Q (Scheme34).

Ethyl1-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-methoxypyridin-4-yl)-4-methyl-1H-pyrazole-3-carboxylate(35.5a)

¹H-NMR (400 MHz, CDCl₃): δ 8.25-8.27 (m, 1H), 7.70-7.71 (m, 1H),7.26-7.30 (m, 1H), 7.14-7.18 (m, 1H), 6.65-6.69 (m, 2H), 4.44 (q, J=7.2Hz, 2H), 4.00 (s, 3H), 2.36 (s, 3H) and 1.41 (t, J=7.2 Hz, 3H). MS:424.04 (M+H)⁺. Yield: 51%.

Ethyl1-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(6-methoxypyridin-3-yl)-4-methyl-1H-pyrazole-3-carboxylate(35.5b)

¹H-NMR (400 MHz, CDCl₃): δ 8.86 (s, 1H), 7.66-7.70 (m, 1H), 7.32-7.35(m, 1H), 7.11-7.16 (m, 1H), 6.79-6.89 (m, 2H), 4.45 (q, J=7.2 Hz, 2H),3.89 (s, 3H), 2.31 (s, 3H) and 1.42 (t, J=7.2 Hz, 3H). MS: 424.15(M+H)⁺. Yield: 38%.

General Procedure for the Preparation of Compounds 35.6(a-b):

These compounds were prepared following the general method R (Scheme34).

1-(4-Fluoro-3-(trifluoromethyl)phenyl)-5-(2-methoxypyridin-4-yl)-4-methyl-1H-pyrazole-3-carboxylicAcid (35.6a)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.01 (br s, 1H), 8.16-8.18 (m, 1H),7.72-7.74 (m, 1H), 7.50-7.55 (m, 2H), 7.74-7.77 (m, 2H), 3.84 (s, 3H)and 2.21 (s, 3H). MS: 396.10 (M+H)⁺. Yield: 77%.

1-(4-Fluoro-3-(trifluoromethyl)phenyl)-5-(6-methoxypyridin-3-yl)-4-methyl-1H-pyrazole-3-carboxylicAcid (35.6b)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.86 (br s, 1H), 8.11 (s, 1H), 7.72-7.75(m, 1H), 7.50-7.57 (m, 3H), 6.86-6.90 (m, 1H), 3.86 (s, 3H) and 2.19 (s,3H). LCMS: 396.02 (M+H)⁺, 95.80%. Yield: 58%.

General Procedure for the Preparation of Compounds 35.7(a-b):

These compounds were prepared following the general method P (Scheme33). The final compounds 35.7a and 35.7b were purified via prep-HPLC.

General Procedure for the Preparation of Compounds 57 (a-b) (GeneralMethod T):

To a solution of compounds 35.7 (a-b) (1.0 eq) in DMF was added LiCl(5.0 eq) and p-TSA (5.0 eq). The resulting reaction mass was heated at130° C. in microwave for 30 min. After the completion of the reaction(TLC monitoring), the solution was diluted with ice-cold water followedby extraction with EtOAc (3 times). The combined organics were washedwith brine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The final compounds 35.8a and 35.8b were purified viaprep-HPLC.

The yields and analytical data of the final compounds are set forth inTable 6.12.

TABLE 6.12 Tabulated data of the final compounds including theindividual yields Com- Amine ¹H-NMR data (DMSO-d₆, 400 poundintermediate Yield MHz), unless otherwise ID Structure used (%) LCMSspecified 301

Intermediate- 3 37 631.27 (M + H)⁺, 99.46% δ 11.25 (br s, 1H), 8.19 (d,J = 5.2 Hz, 1H), 7.73-7.75 (m, 1H), 7.54- 7.58 (m, 2H), 7.00-7.07 (m,1H), 6.73-6.84 (m, 3H), 4.67-4.70 (m, 2H), 4.31-4.35 (m, 1H), 3.85 (s,3H), 3.30-3.32 (m, 1H), 2.93-2.98 (m, 1H), 2.10-2.12 (m, 5H) and1.81-1.91 (m, 2H) 302

Intermediate- 3 44 617.30 (M + H)⁺, 99.49% δ 11.25-11.29 (m, 2H),7.80-7.82 (m, 1H), 7.70-7.72 (m, 1H), 7.60- 7.65 (m, 1H), 7.40 (d, J =6.8 Hz, 1H), 7.00-7.08 (m, 1H), 6.78-6.81 (m, 1H), 6.36 (s, 1H), 5.93(d, J = 6.8 Hz, 1H), 4.68-4.71 (m, 2H), 4.30-4.33 (m, 1H), 3.30-3.32 (m,1H), 2.94-3.00 (m, 1H), 2.14-2.18 (m, 5H) and 1.82-1.92 (m, 2H) 303

Intermediate- 3 36 631.31 (M + H)⁺, 99.90% δ 11.25 (br s, 1H), 8.15 (d,J = 2.0 Hz, 1H), 7.70-7.72 (m, 1H), 7.53- 7.62 (m, 3H), 7.00-7.07 (m,1H), 6.87 (d, J = 8.4 Hz, 1H), 6.77-6.80 (m, 1H), 4.63-4.71 (m, 2H),4.36- 4.39 (m, 1H), 3.87 (s, 3H), 3.30- 3.32 (m, 1H), 2.92-2.99 (m, 1H),2.09-2.12 (m, 5H) and 1.81-1.91 (m, 2H) 304

Intermediate- 3 15 617.27 (M + H)⁺, 99.22% δ 11.98 (br s, 1H), 11.25 (brs, 1H), 7.76-7.78 (m, 1H), 7.68-7.72 (m, 1H), 7.59-7.63 (m, 1H), 7.49(s, 1H), 7.21-7.24 (m, 1H), 7.00- 7.07 (m, 1H), 6.77-6.80 (m, 1H),6.32-6.34 (m, 1H), 4.67-4.70 (m, 2H), 4.32-4.36 (m, 1H), 3.30- 3.32 (m,1H), 2.94-2.98 (m, 1H), 2.07-2.12 (m, 5H) and 1.80-1.90 (m, 2H)

General Procedure for the Preparation of Compounds 36.3(a-b):

These compounds were prepared following the general method O (Scheme33).

4-Ethoxy-3,4-dioxo-1-(pyrazin-2-yl)but-1-en-1-olate Lithium Salt (36.3a)

¹H-NMR (400 MHz, DMSO-d₆): δ 9.13-9.18 (m, 1H), 8.73-8.74 (m, 1H),8.55-8.58 (m, 1H), 7.01 (s, 1H), 4.24 (q, J=6.8 Hz, 2H) and 1.23 (t,J=6.8 Hz, 3H). MS: 223.04 (M+H)⁺. Yield: Quantitative.

4-Ethoxy-3,4-dioxo-1-(1H-pyrrol-3-yl)but-1-en-1-olate Lithium Salt(36.3b)

¹H-NMR (400 MHz, DMSO-d₆): δ 11.08 (br s, 1H), 7.24 (s, 1H), 6.70-6.80(m, 1H), 6.35-6.41 (m, 1H), 6.13 (s, 1H), 4.18 (q, J=7.2 Hz, 2H) and1.26 (t, J=6.8 Hz, 3H). MS: 210.19 (M+H)⁺. Yield: Quantitative.

General Procedure for the Preparation of Compounds 36.5(a-b):

These compounds were prepared following the general method Q (Scheme34).

Ethyl1-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(pyrazin-2-yl)-1H-pyrazole-3-carboxylate(36.5a)

¹H-NMR (400 MHz, CDCl₃): δ 8.80 (s, 1H), 8.54 (s, 1H), 8.37 (s, 1H),7.71-7.72 (m, 1H), 7.50-7.53 (m, 1H), 7.38 (s, 1H), 7.20-7.22 (m, 1H),4.50 (q, J=7.2 Hz, 2H) and 1.46 (t, J=7.2 Hz, 3H). MS: 381.31 (M+H)⁺.Yield: 29%.

Ethyl1-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(1H-pyrrol-3-yl)-1H-pyrazole-3-carboxylate(36.5b)

¹H-NMR (400 MHz, CDCl₃): δ 8.27 (br s, 1H), 7.74-7.78 (m, 1H), 7.57-7.63(m, 1H), 7.20-7.26 (m, 1H), 6.94-6.98 (m, 1H), 6.75 (s, 1H), 6.64 (s,1H), 5.99 (s, 1H), 4.41 (q, J=7.2 Hz, 2H) and 1.40 (t, J=7.2 Hz, 3H).LCMS: 368.22 (M+H)⁺, 96.13%. Yield: 45%.

General Procedure for the Preparation of Compounds 36.6(a-b):

These compounds were prepared following the general method R (Scheme34).

1-(4-Fluoro-3-(trifluoromethyl)phenyl)-5-(pyrazin-2-yl)-1H-pyrazole-3-carboxylicAcid (36.6a)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.24 (br s, 1H), 9.11 (s, 1H), 8.61 (d,J=2.0 Hz, 1H), 8.47 (s, 1H), 7.89-7.90 (m, 1H), 7.79-7.81 (m, 1H) and7.69-7.64 (m, 2H). LCMS: 353.19 (M+H)+, 99.79%. Yield: 59%.

1-(4-Fluoro-3-(trifluoromethyl)phenyl)-5-(1H-pyrrol-3-yl)-1H-pyrazole-3-carboxylicAcid (36.6b)

¹H-NMR (400 MHz, DMSO-d₆): δ 12.88 (br s, 1H), 11.11 (br s, 1H),7.81-7.86 (m, 2H), 7.65-7.69 (m, 1H), 6.90 (s, 1H), 6.75 (s, 2H) and5.86 (s, 1H). LCMS: 340.07 (M+H)+, 99.90%. Yield: 71%.

General Procedure for the Preparation of Final Compounds 36.7:

The final compounds were prepared following the general method P (Scheme33). To an ice-cold solution of carboxylic acid 61 (a-b) (125-150 mg),in DMF (2.0 mL) was added DIPEA (2.5 eq) and HATU (1.50 eq). Theresulting mixture was stirred under nitrogen atmosphere at 0° C. for 15min followed by addition of respective amines (1.20 eq). The reactionmixture was then stirred at room temperature for 16 h. After thecompletion of the reaction (TLC monitoring), the solution was dilutedwith ice-cold water (30 mL) followed by extraction with EtOAc (3×50 mL).The combined organics were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The cruderesidue was purified via prep-HPLC. The final compounds were purifiedvia prep-HPLC.

The yields and analytical data of the final compounds are set forth inTable 6.13.

TABLE 6.13 Tabulated data of the final compounds including theindividual yields Amine ¹H-NMR data (DMSO-d₆, 400 Compound intermediateYield MHz), unless otherwise ID Structure used (%) LCMS specified 305

Intermediate- 3 24 588.29 (M + H)⁺ 99.45% δ 11.25 (br s, 1H), 9.11 (s,1H), 8.61-8.62 (m, 1H), 8.48-8.49 (m, 1H), 7.88-7.90 (m, 1H), 7.80-7.84(m, 1H), 7.58-7.63 (m, 1H), 7.50 (s, 1H), 7.00-7.06 (m, 1H), 6.77-6.80(m, 1H), 4.76-4.79 (m, 1H), 4.63-4.68 (m, 2H), 3.31-3.32 (m, 1H),2.93-2.99 (m, 1H), 2.12-2.17 (m, 2H) and 1.83-1.92 (m, 2H) 306

Intermediate- 1 28 584.33 (M + H)⁺ 99.28% δ 9.09 (s, 1H), 8.80 (s, 1H),8.61-8.62 (m, 1H), 8.48-8.49 (m, 1H), 7.86-7.88 (m, 2H), 7.56-7.61 (m,1H), 7.48 (s, 1H), 7.07-7.12 (m, 2H), 6.83-6.87 (m, 2H), 4.58 (s, 2H),4.42- 4.45 (m, 2H), 3.35-3.38 (m, 1H), 3.51-3.54 (m, 1H), 2.21- 2.33 (m,2H) and 1.72-1.83 (m, 2H) 307

Intermediate- 3 6 575.36 (M + H)⁺ 98.10% δ 11.10 (br s, 2H), 7.83-7.86(m, 2H), 7.63-7.65 (m, 1H), 6.99-7.06 (m, 1H), 6.76-6.79 (m, 4H),5.86-5.88 (m, 1H), 4.82-4.86 (m, 1H), 4.60-4.68 (m, 2H), 3.25-3.28 (m,1H), 2.88-2.93 (m, 1H), 2.11-2.17 (m, 2H) and 1.75-1.89 (m, 2H) 308

Intermediate- 1 16 571.39 (M + H)⁺ 99.82% δ 11.10 (br s, 1H), 8.78-8.81(m, 1H), 7.79-7.83 (m, 2H), 7.61-7.66 (m, 1H), 7.06-7.11 (m, 2H),6.82-6.86 (m, 2H), 6.76-6.79 (m, 3H), 5.86-5.88 (m, 1H), 4.58 (s, 2H),4.39- 4.50 (m, 2H), 3.79-3.84 (m, 1H), 3.47-3.52 (m, 1H), 2.17- 2.25 (m,2H) and 1.70-1.80 (m, 2H)

Preparation of 1-(1-benzyl-1H-imidazol-4-yl)ethan-1-one (37.3)

To an ice-cold solution of 1-(1H-imidazol-4-yl)ethan-1-one 37.1 (5.0 g,45.43 mmol) in THF (50 mL) was added NaH (60% dispersion in mineral oil,2.72 g, 68.15 mmol) portion-wise, followed by addition of benzyl bromide37.2 (6.51 mL, 54.52 mmol). The resulting reaction mixture was stirredat RT for 16 h. After the completion of the reaction (TLC monitoring),the solution was diluted with ice-cold water (100 mL) followed byextraction with EtOAc (3×100 mL). The combined organics were washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The crude was purified over silica gel (100-200 M),elution with 25% EtOAc/hexane to get desired product 37.3 (4.5 g, Yield:49%) as off white solid. ¹H-NMR (400 MHz, CDCl₃): δ 7.67 (s, 1H), 7.57(s, 1H), 7.37-7.41 (m, 3H), 7.19-7.21 (m, 2H), 5.16 (s, 2H) and 2.56 (s,3H). LCMS: 201.13 (M+H)⁺, 98.80%.

Preparation of1-(1-benzyl-1H-imidazol-4-yl)-4-ethoxy-3,4-dioxobut-1-en-1-olate LithiumSalt (37.5)

This compound was prepared following the general method O (Scheme 33).¹H-NMR (400 MHz, DMSO-d₆): δ 7.78 (s, 1H), 7.61 (s, 1H), 7.12-7.34 (m,5H) and 6.58 (s, 1H), 5.20 (s, 2H), 4.12 (q, J=6.8 Hz, 2H) and 1.21 (t,J=7.2 Hz, 3H). MS: 301.13 (M+H)⁺.

Preparation of ethyl5-(1-benzyl-1H-imidazol-4-yl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylate(37.7)

This compound was prepared following the general method Q (Scheme 34).¹H-NMR (400 MHz, CDCl₃): δ 7.85-7.93 (s, 2H), 7.81 (s, 1H), 7.61-7.66(m, 1H), 7.30-7.38 (m, 4H), 7.20-7.25 (m, 2H), 7.06 (s, 1H), 5.17 (s,2H), 4.31 (q, J=6.8 Hz, 2H) and 1.30 (t, J=7.2 Hz, 3H). MS: 459.15(M+H)⁺. Yield: 51%.

Preparation of5-(1-benzyl-1H-imidazol-4-yl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylicAcid (37.8)

This compound was prepared following the general method R (Scheme 11).¹H-NMR (400 MHz, DMSO-d₆): δ 13.14 (br s, 1H), 8.46 (s, 1H), 7.86-7.91(m, 2H), 7.63-7.67 (m, 1H), 7.34-7.36 (m, 4H), 7.24-7.25 (m, 2H), 7.17(s, 1H) and 5.26 (s, 2H). LCMS: 431.17 (M+H)⁺, 93.47%. Yield: 64%.

General Procedure for the Preparation of Final Compounds 37.10(a-b):

The final compounds were prepared following the general method P (Scheme33). The final compounds 37.10a and 37.10b were purified via prep-HPLC.Please refer to Table 14 for individual yields and the analytical dataof the final compounds.

General Procedure for the Preparation of Compounds 37.11(a-b):

The final compounds were prepared following the general method E (Scheme1). The final compounds 37.11a and 37.11b were purified via prep-HPLC.

The yields and analytical data of the final compounds are set forth inTable 6.14.

TABLE 6.14 Tabulated data of the final compounds including theindividual yields Amine ¹H-NMR data (DMSO-d₆, 400 Compound intermediateYield MHz), unless otherwise ID Structure used (%) LCMS specified 309

Intermediate- 3 24 576.33 (M + H)⁺ 95.60% δ 11.25 (br s, 1H, D₂Oexchangeable), 8.50 (br s, 1H), 8.79 (s, 1H), 7.87-7.93 (m, 2H),7.63-7.68 (m, 1H), 7.37 (s, 1H), 7.02-7.07 (m, 2H), 6.77-6.80 (m, 1H),4.80 (d, J = 14.0 Hz, 1H), 4.62-4.68 (m, 2H), 3.29-3.35 (m, 2H),2.91-2.97 (m, 1H), 2.12-2.15 (m, 2H) and 1.82-1.91 (m, 2H) 310

Intermediate- 1 20 572.34 (M + H)⁺ 98.43% δ 12.37 (br s, 1H), 8.79 (s,1H), 7.81-7.85 (m, 2H), 7.70 (s, 1H), 7.57-7.62 (m, 1H), 7.30 (m, 1H),7.06-7.11 (m, 2H), 6.92 (s, 1H), 6.83-6.86 (m, 2H), 4.58 (s, 2H),4.40-4.49 (m, 2H), 3.80-3.85 (m, 1H), 3.48-3.54 (m, 1H), 2.18-2.33 (m,2H) and 1.70-1.81 (m, 2H) 311

Intermediate- 3 15 666.39 (M + H)⁺ 99.81% δ 11.20 (br s, 1H), 7.82-7.89(m, 3H), 7.59-7.63 (m, 1H), 7.28-7.37 (m, 4H), 7.20-7.22 (m, 2H), 6.99-7.06 (m, 1H), 6.88 (s, 1H), 6.76- 6.79 (m, 1H), 5.19 (s, 2H), 4.79 (d, J= 12.80 Hz, 1H), 4.60-4.67 (m, 2H), 3.25-3.29 (m, 1H), 2.88- 2.95 (m,1H), 2.11 (m, 2H) and 1.80-1.89 (m, 2H) 312

Intermediate- 1 13 662.44 (M + H)⁺ 99.72% δ 8.78 (br s, 1H), 7.81-7.85(m, 3H), 7.57-7.61 (m, 1H), 7.28-7.37 (m, 4H), 7.20-7.22 (m, 2H), 7.06-7.10 (m, 2H), 6.88 (s, 1H), 6.84- 6.86 (m, 2H), 5.19 (s, 2H), 4.57 (brs, 2H), 4.40-4.45 (m, 2H), 3.78-3.84 (m, 1H), 3.47-3.52 (m, 1H),2.19-2.28 (m, 2H) and 1.69- 1.80 (m, 2H)

General Method A2 for the Preparation of Compounds 38.2 (a-b):

To an ice-cold solution of 1-benzylpiperidin-4-one 1 (5.0-7.0 g, 1.0 eq)in acetic acid was added respective amines (1.1 eq) and trimethylsilylcyanide (1.5 eq). The resulting reaction mass was stirred at RT for 18h. After completion of the reaction (TLC monitoring), the reaction masswas cooled to 0° C. and the pH adjusted to ˜10 using 5.0 N sodiumhydroxide solution. The aqueous part was extracted with DCM (3×250 mL).The combined organics were dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude was triturated with diethyl ether to obtain thedesired product 38.2 (a-b) as off white solid.

1-Benzyl-4-((4-fluorophenyl)amino)piperidine-4-carbonitrile (38.2-a)

¹H-NMR (400 MHz, CDCl₃): δ 7.35-7.38 (m, 5H), 6.90-6.95 (m, 4H), 3.54(s, 2H), 3.48 (br s, 1H), 2.80-2.84 (m, 2H), 2.38-2.41 (m, 2H),2.22-2.24 (m, 2H) and 1.89-1.94 (m, 2H). LC-MS: 310.23 (M+H)+, 95.66%.Yield: 58%.

1-Benzyl-4-((4-fluoro-3,5-dimethylphenyl)amino)piperidine-4-carbonitrile(38.2-b)

¹H-NMR (400 MHz, CDCl₃): δ 7.26-7.31 (m, 5H), 6.55-6.57 (m, 1H),6.37-6.38 (m, 1H), 3.60 (s, 1H), 3.53 (s, 2H), 2.76-2.81 (m, 2H),2.45-2.50 (m, 2H), 2.28-2.32 (m, 2H), 2.09 (m, 6H), and 1.88-1.93 (m,2H). MS: 338.33 (M+H)⁺, Yield: 60%.

General Method B2 for the Preparation of Compounds 38.3 (a-b):

An ice-cold solution of 38.2 (a-b) (3.0-4.0 g, 1.0 eq) in 90% aqueoussulphuric acid was stirred at 0° C. for 30.0 min, then warm up to RT andstirred for 16 h. After completion of the reaction (TLC monitoring), thereaction mass was cooled to 0° C. and the pH adjusted to ˜10 using 5.0 Nsodium hydroxide solution. The aqueous part was extracted with DCM. Thecombined organics were dried over anhydrous sodium sulphate, filteredand concentrated. The crude was triturated with diethyl ether to obtainthe desired product 3 (a-b) as off-white solid.

1-Benzyl-4-(4-fluorophenylamino)piperidine-4-carboxamide (38.3-a)

¹H-NMR (400 MHz, CDCl₃): δ 7.23-7.25 (m, 5H), 6.85-6.87 (m, 3H),6.54-6.55 (m, 2H), 5.47 (br s, 1H), 3.93 (s, 1H), 3.48 (s, 2H),2.72-2.74 (m, 2H), 2.28-2.29 (m, 2H), 2.04-2.07 (m, 2H) and 1.86-1.89(m, 2H). LCMS: 328.22 (M+H)⁺, 98.42%. Yield: 84%.

1-Benzyl-4-((4-fluoro-3,5-dimethylphenyl)amino)piperidine-4-carboxamide(38.3-b)

¹H-NMR (400 MHz, CDCl₃): δ 7.28-7.34 (m, 6H), 7.15 (br s, 1H), 7.01 (s,1H), 6.21-6.27 (m, 2H), 3.48 (s, 2H), 2.50-2.51 (m, 2H), 2.22-2.24 (m,2H), 2.06 (d, J=6.0 Hz, 6H), 1.96-1.99 (m, 2H) and 1.77-1.81 (m, 2H).MS: 356.37 (M+H)⁺. Yield: 56.6%.

General Method C2 for the Preparation of Compounds 38.4 (a-c):

To a solution of compounds 38.3 (a-b) (1.0-2.5 g, 1.0 eq) in methanolwas added DMF-DMA (3.0 eq). The resulting reaction mass was heated at65° C. for h. After completion of reaction (TLC monitoring), the solventwas evaporated to dryness. The resulting crude residue was trituratedwith diethyl ether to get off white solid product 38.4 (a-b).

8-Benzyl-1-(4-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one(38.4-a)

H-NMR (400 MHz, DMSO-d₆): δ 8.65 (s, 1H), 7.44-7.46 (m, 2H), 7.31-7.34(m, 2H), 7.13-7.16 (m, 5H), 3.41 (s, 2H), 2.66-2.69 (m, 2H), 2.41-2.44(m, 2H) and 1.75-1.78 (m, 4H). MS: 338.22 (M+H)⁺. Yield: 89%.

8-Benzyl-1-(4-fluoro-3,5-dimethylphenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one(38.4-b)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.15 (s, 1H), 7.48-7.49 (m, 4H), 7.26-7.28(m, 1H), 7.80-7.81 (m, 2H), 3.60 (s, 2H), 2.87-2.91 (m, 2H), 2.59-2.61(m, 2H), 2.28 (s, 6H), 1.88-1.89 (m, 2H) and 1.56-1.58 (m, 2H). MS:366.35 (M+H)⁺. Yield: 79%.

General Method D2 for the Preparation of Compounds 38.5 (a-b):

To a solution of compounds 38.4 (a-b) (0.50-1.5 g, 1.0 eq) in MeOH andAcOH (40:1, 20 mL) were added Pd—C (10 mol % w/w) and the resultingsolution was stirred under hydrogen atmosphere (1 atm) at ambienttemperature for 16 h. The reaction mixture was filtered through adiatomaceous earth (Celite) bed and the filtrate was concentrated underreduced pressure. The residue was purified over silica gel (basicalumina, 2-4% MeOH-DCM) to obtain the desired product 38.5 (a-b) as offwhite solid.

1-(4-Fluorophenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one (38.5-a;Intermediate 1.2)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.81 (br s, 1H), 7.05-7.08 (m, 2H),6.95-6.96 (m, 2H), 4.58 (s, 2H), 3.34-3.37 (m, 3H), 2.97-2.99 (m, 2H),2.35-2.36 (m, 2H) and 1.61-1.63 (m, 2H). LCMS: 250.23 (M+H)⁺, 88.25%.Yield: 90%.

1-(4-Fluoro-3,5-dimethylphenyl)-1,3,8-triazaspiro[4.5]decan-4-one(38.5-b; Intermediate 2.2)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.83 (s, 1H), 7.66-7.68 (m, 1H), 6.60-6.66(m, 2H), 4.54 (s, 2H), 3.38-3.41 (m, 2H), 3.12-3.16 (m, 2H), 2.50-2.53(m, 2H), 2.19 (s, 6H) and 1.67-1.70 (m, 2H). MS: 278.32 (M+H)⁺. Yield:80%.

Preparation of1-benzyl-4-((3,5-dichloro-4-fluorophenyl)amino)piperidine-4-carbonitrile39.7

Prepared following general method A2. ¹H-NMR (400 MHz, CDCl₃): δ7.29-7.35 (m, 5H), 6.84-6.85 (m, 2H), 3.62 (s, 1H), 3.56 (s, 2H),2.76-2.80 (m, 2H), 2.45-2.47 (m, 2H), 2.27-2.30 (m, 2H) and 1.86-1.91(m, 2H). MS: 378.26 (M+H)⁺, Yield: 47%.

Preparation of1-benzyl-4-((3,5-dichloro-4-fluorophenyl)amino)piperidine-4-carboxamide39.8

Prepared following general method B2. ¹H-NMR (400 MHz, DMSO-d₆): δ7.15-7.39 (m, 8H), 6.63-6.65 (m, 2H), 3.56-3.60 (m, 2H), 2.66-2.71 (m,2H), 2.26-2.32 (m, 2H), 2.09-2.12 (m, 2H) and 1.80-1.90 (m, 2H). MS:396.30 (M+H)⁺, Yield: 68%.

Preparation of8-benzyl-1-(3,5-dichloro-4-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one39.9

Prepared following general method C2. MS: 405.99 (M+H)⁺. Yield: 80%.

Preparation of8-benzyl-1-(3,5-dichloro-4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one39.10

To an ice-cold solution of8-benzyl-1-(3,5-dichloro-4-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-2-en-4-one39.9 (1.0 eq) in methanol was added NaBH₄ (2.5 eq) portion-wise. Theresulting reaction mixture was stirred at RT for 2 h. After completionof reaction (TLC monitoring), cooled to 0° C. added water and extractedwith EtOAc (3 times). The combined organics were washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated. The crude wastriturated with diethyl ether to get desired product 10 as off whitesolid. ¹H-NMR (400 MHz, DMSO-d₆): δ 8.74 (br s, 1H), 7.31-7.35 (m, 4H),7.24-7.26 (m, 1H), 6.95-6.96 (m, 2H), 4.58 (s, 2H), 3.53-3.54 (m, 2H),2.73-2.74 (m, 2H), 2.63-2.68 (m, 2H), 2.32-2.40 (m, 2H) and 1.57-1.60(m, 2H). LCMS: 408.29 (M+H)⁺, 90.02%. Yield: 57%.

Preparation of1-(3,5-dichloro-4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one 39.11(Intermediate 3.2)

To an ice-cold solution of8-benzyl-1-(3,5-dichloro-4-fluorophenyl)-1,3,8-triazaspiro[4.5]decan-4-one39.10 (1.0 eq) in DCE was added 1-chloroethyl chloroformate (2.0 eq).The resulting reaction mixture was refluxed for 5 h. After completion ofreaction (TLC monitoring), solvent was evaporated to dryness. The cruderesidue was dissolved in MeOH and heated at 65° C. for 16 h. Aftercompletion of reaction (TLC monitoring), solvent was evaporated. Thecrude was purified over silica gel (100-200M), elution with 5% MeOH/DCMto get desired product 39.11 as an off-white solid. ¹H-NMR (400 MHz,DMSO-d₆): δ 9.10 (s, 1H), 8.89-9.03 (m, 1H), 7.08-7.14 (m, 2H), 4.62 (s,2H), 3.54-3.57 (m, 2H), 3.15-3.17 (m, 2H), 2.60-2.64 (m, 2H) and1.81-1.90 (m, 2H). MS: 318.23 (M+H)⁺. Yield: 60%.

Preparation of8-benzyl-3-((4-fluorophenyl)amino)-8-azabicyclo[3.2.1]octane-3-carbonitrile(40.13)

Prepared following general method A2. MS: 336.14 (M+H)⁺. Yield: 32%.

Preparation of8-benzyl-3-((4-fluorophenyl)amino)-8-azabicyclo[3.2.1]octane-3-carboxamide(40.14)

Prepared following general method B2. ¹H-NMR (400 MHz, DMSO-d₆): δ 7.63(br s, 1H), 7.46-7.52 (m, 2H), 7.41-7.46 (m, 2H), 7.26-7.30 (m, 3H),6.87-6.91 (m, 2H), 6.59 (br s, 2H), 5.44 (m, 1H), 4.15 (m, 1H),3.83-3.85 (s, 2H), 3.37-3.40 (m, 2H), 2.72-2.78 (m, 2H), 2.12-2.17 (m,2H) and 1.80-1.90 (m, 2H). LCMS: 354.36 (M+H)⁺, 93.06%. Yield: 45%.

Preparation of8-benzyl-3′-(4-fluorophenyl)-8-azaspiro[bicycle[3.2.1]octane-3,4′-imidazol]-5′(3′H)-one(40.15)

Prepared following general method C2. MS: 363.98 (M+H)⁺. Yield: 50%.

Preparation of3′-(4-fluorophenyl)-8-azaspiro[bicyclo[3.2.1]octane-3,4′-imidazolidin]-5′-one40.16 (Intermediate 4.2)

Prepared following the general method D2. MS: 276.18 (M+H)⁺. Yield: 29%.

General Method E2: For the Preparation of Compounds 41.19 (a-b):

To an ice-cold solution of tert-butyl 4-aminopiperidine-1-carboxylate41.18 (1.0-2.5 g, 1.0 eq) in DMF was added DIPEA (1.5 eq) and respectivenitro compounds 41.17 (a-b) (1.0 eq). The resulting reaction mixture wasstirred at RT for 2-3 h. After completion of the reaction (TLCmonitoring), the reaction mass was diluted with ice-cold water andextracted with EtOAc (3 times). The combined organics were washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated. The crudewas purified over silica gel (100-200 M, 10-15% EtOAc-hexane) to obtainthe desired product 41.19 (a-b).

tert-Butyl 4-((2,3-difluoro-6-nitrophenyl)amino)piperidine-1-carboxylate(41.19-a)

¹H-NMR (400 MHz, CDCl₃): δ 8.00-8.04 (m, 1H), 7.94 (d, J=8.0 Hz, 1H),6.48-6.54 (m, 1H), 4.01-4.02 (m, 3H), 2.94-2.99 (m, 2H), 2.04-2.06 (m,2H) and 1.46-1.49 (m, 11H). LCMS: 356.52 (M−H)⁺, 99.10%. Yield: 56%.

tert-Butyl 4-((5-cyano-2-nitrophenyl)amino)piperidine-1-carboxylate(41.19-b)

¹H-NMR (400 MHz, CDCl₃): δ 8.25 (d, J=8.8 Hz, 1H), 8.25 (m, J=7.2 Hz,1H), 7.17 (s, 1H), 6.86 (d, J=8.8 Hz, 1H), 4.04-4.10 (m, 2H), 3.60-3.67(m, 1H), 3.03-3.08 (m, 2H), 2.03-2.07 (m, 2H), 1.57-1.63 (m, 2H) and1.51 (s, 9H). LCMS: 345.22 (M−H)⁺, 99.0%. Yield: 75.3%.

General Method F2 for the Preparation of Compounds 41.20 (a-b):

To a solution of compound 41.19 a (1.0-2.5 g, 1.0 eq) in EtOAc wereadded Pd—C (w/w, 10 mol %) and the resulting solution was stirred underhydrogen atmosphere (1 atm) at ambient temperature for 16 h. Thereaction mixture was filtered through a diatomaceous earth (Celite) bedand the filtrate was concentrated under reduced pressure to obtain thedesired product 41.20a.

tert-Butyl 4-((6-amino-2,3-difluorophenyl)amino)piperidine-1-carboxylate(41.20-a)

¹H-NMR (400 MHz, DMSO-d₆): δ 6.58-6.65 (m, 1H), 6.33-6.36 (m, 1H), 4.80(br s, 2H), 3.87-4.05 (m, 3H), 3.17-3.20 (m, 1H), 2.73-2.75 (m, 2H),1.73-1.76 (m, 2H), 1.39 (s, 9H) and 1.23-1.25 (m, 2H). LCMS: 328.41(M+H)⁺, 97.70%. Yield: 97%.

General Method G2:

To a solution of compound 41.19-b (1.0-2.0 g, 1.0 eq) in MeOH were addedammonium formate (5.0 eq) and Pd—C (w/w, 10 mol %) and the resultingsolution was stirred under at RT for 3-4 h. The reaction mixture wasfiltered through a diatomaceous earth (Celite) bed and the filtrate wasconcentrated under reduced pressure to obtain the desired product41.20-b.

tert-Butyl 4-((2-amino-5-cyanophenyl)amino)piperidine-1-carboxylate(41.20-b)

¹H-NMR (400 MHz, CDCl₃): δ 7.01 (d, J=8.8 Hz, 1H), 6.87 (s, 1H), 6.68(d, J=8.8 Hz, 1H), 4.05-4.10 (br s, 3H), 3.36-3.39 (m, 1H), 2.91-2.94(m, 2H), 2.00-2.03 (m, 4H) and 1.40 (s, 11H). MS: 317.39 (M+H)⁺. Yield:85%.

General Method H2 for the Preparation of Compounds 41.21 (a-b):

To an ice-cold solution of compound 41.20 (a-b) (0.50-1.50 g, 1.0 eq) inTHF was added Et₃N (2.0 eq) and triphosgene (1.5 eq). The resultingreaction mixture was stirred at RT for 4 h. After completion of thereaction (TLC monitoring), the solvent was evaporated and the residuewas diluted with water and extracted with ethyl acetate (3 times). Thecombined organics were washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated. The crude was purified over silica gel(100-200 M, 30-40% EtOAc-hexane) to obtain the desired product 41.21(a-b).

tert-Butyl4-(6,7-difluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate(41.21-a)

¹H-NMR (400 MHz, DMSO-d₆): δ 11.24 (br s, 1H), 7.02-7.06 (m, 1H),6.76-6.79 (m, 1H), 4.47-4.52 (m, 1H), 3.99-4.05 (m, 2H), 2.87-2.89 (m,2H), 1.90-1.98 (m, 2H), 1.71-1.74 (m, 2H) and 1.42 (s, 9H). LCMS: 354.55(M+H)⁺, 86.20%. Yield: 92%.

tert-Butyl4-(6-cyano-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate(41.21-b)

¹H-NMR (400 MHz, CDCl₃): δ 10.01 (br s, 1H), 7.38-7.41 (m, 2H), 7.16 (d,J=8.0 Hz, 1H), 4.37-4.45 (m, 3H), 2.84-2.90 (m, 2H), 2.30-2.35 (m, 2H),1.83-1.85 (m, 2H) and 1.52 (s, 9H). LCMS: 343.37 (M+H)⁺, 86.18%. Yield:60%.

General Method 12 for the Preparation of Compounds 41.22 (a-b):

An ice-cold solution of compound 41.21 (a-b) (0.5 g-1.0 g) indioxane-HCl (˜4N) was stirred at RT for 2 h. After completion of thereaction (TLC monitoring), the reaction mass was dried under reducedpressure. The crude was triturated with diethyl ether to get desiredproduct 41.22 (a-b) as off solid.

6,7-Difluoro-1-(piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-oneHydrochloride 41.22-a (Intermediate 5.2)

¹H-NMR (400 MHz, DMSO-d₆): δ 11.38 (br s, 1H), 9.44 (br s, 1H), 8.65 (brs, 1H), 7.01-7.07 (m, 1H), 6.78-6.79 (m, 1H), 4.58-4.60 (m, 1H),3.63-3.65 (m, 2H), 2.45-3.49 (m, 2H), 3.03-3.12 (m, 2H) and 2.35-2.38(m, 2H). LCMS: 254.11 (M+H)⁺, 95.61%. Yield: quantitative.

2-Oxo-3-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrileHydrochloride 41.22-b (Intermediate 6.2)

¹H-NMR (400 MHz, DMSO-d₆): δ 11.55 (br s, 1H), 8.93 (br s, 1H), 8.75 (brs, 1H), 7.86 (s, 1H), 7.47 (d, J=7.2 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H),4.57-4.60 (m, 1H), 3.35-3.40 (m, 2H), 3.04-3.08 (m, 2H), 2.55-2.61 (m,2H) and 1.85-1.88 (m, 2H). LCMS: 243.32 (M+H)⁺, 98.82%. Yield: 85%.

Preparation of tert-butyl3-((2,3-difluoro-6-nitrophenyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate(42.24)

Prepared following the general method E2. ¹H-NMR (400 MHz, CDCl₃): δ8.61 (d, J=6.0 Hz, 1H), 8.01-8.04 (m, 1H), 6.45-6.51 (m, 1H), 4.21-4.31(m, 3H), 2.29-2.35 (m, 2H), 2.07-2.09 (m, 2H), 1.94-1.96 (m, 2H),1.68-1.73 (m, 2H) and 1.47 (s, 9H). LCMS: 384.36 (M+H)⁺, 99.35%. Yield:78%.

Preparation of tert-butyl3-((6-amino-2,3-difluorophenyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate(42.25)

Prepared following the general method F2. ¹H-NMR (400 MHz, DMSO-d₆): δ6.57-6.60 (m, 1H), 6.39-6.41 (m, 1H), 4.70 (br s, 2H), 4.17-4.19 (m,1H), 4.01-4.08 (m, 2H), 3.64 (br s, 1H), 1.98-2.06 (m, 4H), 1.84-1.86(m, 2H), 1.61-1.64 (m, 2H) and 1.38 (s, 9H). MS: 354.13 (M+H)⁺. Yield:95%.

Preparation of tert-butyl3-(6,7-difluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate(42.26)

Prepared following the general method H2. ¹H-NMR (400 MHz, CDCl₃): δ10.03 (br s, 1H), 6.85-6.97 (m, 1H), 6.74-6.75 (m, 1H), 4.52-4.59 (m,1H), 4.34-4.46 (m, 2H), 2.52-2.54 (m, 2H), 2.06-2.10 (m, 2H), 1.80-1.89(m, 4H) and 1.52 (s, 9H). LCMS: 378.13 (M−H)+, 96.51%. Yield: 85%.

Preparation of1-(8-azabicyclo[3.2.1]octan-3-yl)-6,7-difluoro-1,3-dihydro-2H-benzo[d]imidazol-2-oneHydrochloride 42.27 (Intermediate 7.2)

Prepared following general method 12. ¹H-NMR (400 MHz, DMSO-d₆): δ 11.34(br s, 1H), 9.02 (br s, 1H), 8.87 (br s, 1H), 7.03-7.10 (m, 1H),6.80-6.81 (m, 1H), 4.89-4.93 (m, 1H), 4.08-4.10 (m, 2H), 2.49-2.52 (m,2H), 2.08-2.09 (m, 2H) and 1.90-1.97 (m, 4H). LCMS: 278.06 (M−H)⁺,99.73%. Yield: 94%.

Synthesis of Final Compounds

General Method J2 for the Preparation of Compounds 43.30 (a-b):

A solution of compound 43.28 (a-b) (1.0 eq) in di-ethyl ether was cooledto −78° C. followed by addition of LiHMDS (1.0 M in THF, 2.5 eq). Theresulting reaction mixture was stirred at −78° C. for 45 min followed bydrop wise addition of diethyl oxalate 43.29 (1.2 eq). The reactionmixture was then left to stir at room temperature for 16 h. Aftercompletion of the reaction (TLC and MS monitoring), the solution wasthen cooled to 0° C. and the resulting precipitate was filtered toobtain the desired product 43.30 (a-b) as an off-white solid, which wascarried forward to the next step without purification.

2-Ethoxy-2-oxo-1-(5-oxo-7,8-dihydroquinolin-6(5H)-ylidene)ethan-1-olateLithium Salt (43.30-a)

MS: 248.24 (M+H)⁺. Yield: 56%.

2-Ethoxy-2-oxo-1-(8-oxo-5,8-dihydroquinolin-7(6H)-ylidene)ethan-1-olateLithium Salt (43.30-b)

MS: 248.16 (M+H)⁺. Yield: 60%.

General Method K2 for the Preparation of Compounds 43.31 (a-b):

To an ice-cold solution of lithium salt of compound 43.30 (a-b) (1.0 eq)in IPA was added (4-fluoro-3-(trifluoromethyl)phenyl)hydrazine (1.2 eq)and TFA (2.0 eq). The resulting reaction mixture was warm up to roomtemperature and then stirred at 90° C. for 4-5 h. After completion ofthe reaction (TLC monitoring), the solvent was evaporated and theresidue was diluted with water and extracted with ethyl acetate (3times). The combined organics were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated. The crude waspurified over silica gel (100-200 M, 10-15% EtOAc-hexane) to obtain thedesired product 43.31 (a-b).

Ethyl1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazolo[3,4-f]quinoline-3-carboxylate(43.31a)

¹H-NMR (400 MHz, CDCl₃): δ 8.40 (d, J=8.0 Hz, 1H), 8.08-8.09 (m, 1H),7.99-8.01 (m, 1H), 7.72 (t, J=7.2 Hz, 1H), 7.18-7.21 (m, 1H), 7.06-7.14(m, 1H), 4.36 (q, J=7.6 Hz, 2H), 3.09-3.17 (m, 4H) and 1.33 (t, J=7.2Hz, 3H). MS: 406.32 (M+H)⁺. Yield: 40%.

Ethyl1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylate(43.31b)

MS: 406.0 (M+H)⁺. Yield: 7%.

General Method L2 for the Preparation of Compounds 43.32 (a-b):

To an ice-cold solution of ethyl1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate43.31 (a-b) (8.0 g, 21.09 mmol) in EtOH (60 mL) was added drop wise anaqueous solution of sodium hydroxide (1.68 g, 42.18 mmol) in 8 mL H₂O.The resulting solution was stirred at room temperature for 2 h. Aftercompletion of the reaction (TLC monitoring), the solvent was evaporated,added H₂O to the residue followed by extraction with EtOAc (2×100 mL).The organic layer was discarded and the pH of the aqueous layer wasadjusted to ˜4 by adding 1N HCl. The resulting precipitate was filteredand dried under vacuum to obtain the desired product 43.32 (a-b) (4.5 g,61%) as a white solid.

1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazolo[3,4-f]quinoline-3-carboxylicAcid (43.32a)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.05 (br s, 1H), 8.39 (s, 1H), 7.99-8.07(m, 2H), 7.77 (s, 1H), 7.06-7.16 (m, 2H) and 3.07-3.14 (m, 4H). LCMS:378.29 (M+H)⁺, 88.67%. Yield: 45%.

1-(4-fluoro-3-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazolo[4,3-h]quinoline-3-carboxylicAcid (43.32b)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.10 (br s, 1H), 7.96-8.16 (m, 2H),7.62-7.74 (m, 2H), 7.21-7.24 (m, 1H), 7.02-7.07 (m, 1H) and 3.03-3.14(m, 4H). MS: 378.20 (M+H)⁺. Yield: 40%.

General Method M2 for the Preparation of Compounds of General Structure43.33:

To an ice-cold solution of1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicacid 43.32 (a-b) (0.150 g, 0.43 mmol), in DMF (2.0 mL) was added DIPEA(2.5 eq) and HATU (1.50 eq). The resulting mixture was stirred undernitrogen atmosphere at 0° C. for 15 min followed by addition ofrespective amines (1.20 eq). The reaction mixture was then stirred atroom temperature for 16 h. After the completion of the reaction (TLCmonitoring), the solution was diluted with ice-cold water (30 mL)followed by extraction with EtOAc (3×50 mL). The combined organics werewashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude residue was purified viaprep-HPLC. The yields and analytical data of the final compounds are setforth in Table 16.15.

TABLE 6.15 Tabulated data of the final compounds including theindividual yields Amine ¹H-NMR data (DMSO-d₆, Compound IntermediateYield 400 MHz), unless otherwise ID Structure used (%) LCMS specified313

Int 1.2 18% 609.24 (M − H)⁺, 95.20% (DMSO-d₆ + D₂O): δ 8.29 (m, 1H),7.92 (m, 1H), 7.84- 7.86 (m, 1H), 7.60-7.64 (m, 1H), 7.09-7.11 (m, 1H),7.01- 7.05 (m, 3H), 6.83-6.84 (m, 2H), 4.59 (s, 2H), 4.32-4.44 (m, 2H),3.70-3.76 (m, 1H), 3.47-3.51 (m, 1H), 3.02-3.13 (m, 2H), 2.80-2.88 (m,2H), 2.18-2.25 (m, 2H) and 1.65- 1.81 (m, 2H) 314

Int 5.2 22% 613.20 (M + H)⁺ , 99.50% (DMSO-d₆ + D₂O): δ 8.38- 8.40 (m,1H), 7.97-7.99 (m, 1H), 7.91-7.94 (m, 1H), 7.64- 7.69 (m, 1H), 7.27-7.34(m, 2H), 6.99-7.06 (m, 1H), 6.84- 6.83 (m, 1H), 4.62-4.64 (m, 2H),4.49-4.52 (m, 1H), 3.19- 3.30 (m, 3H), 2.89-2.96 (m, 3H), 2.0-2.08 (m,2H) and 1.79-1.89 (m, 2H) 315

Int 1.2  7% 609.22 (M + H)⁺, 99.48% δ 8.80 (s, 1H), 8.17-8.18 (m, 1H),7.93-7.98 (m, 2H), 7.78 (d, J = 7.60 Hz, 1H), 7.59- 7.64 (m, 1H),7.22-7.25 (m, 1H), 7.06-7.11 (m, 2H), 6.83- 6.86 (m, 2H), 4.59 (s, 2H),4.30-4.44 (m, 2H), 3.78-3.84 (m, 1H), 3.49-3.54 (m, 1H), 3.04-3.07 (m,2H), 2.84-2.89 (m, 2H), 2.21-2.36 (m, 2H) and 1.69-1.82 (m, 2H) 316

Int 5.2  4% 613.20 (M + H)⁺, 96.24% (MeOD): δ 8.17-8.18 (m, 1H),7.86-7.92 (m, 2H), 7.72- 7.74 (m, 1H), 7.41-7.46 (m, 1H), 7.19-7.22 (m,1H), 6.94- 7.01 (m, 1H), 6.80-6.83 (m, 1H), 3.34 (m, 1H), 2.97-3.13 (m,4H), 2.35-2.40 (m, 2H), 1.87-2.03 (m, 2H) and 1.26- 1.40 (m, 4H)

General Procedure for the Preparation of Compounds 44.35 (a-c):

A solution of compounds 44.34 (a-c) (1.0 eq) in di-ethyl ether (250 mL)was cooled to −78° C. followed by addition of LiHMDS (1.1 eq). Theresulting reaction mixture was stirred at −78° C. for 45 min followed bydrop wise addition of diethyl oxalate 29 (1.2 eq) in about 20 min. Thereaction mixture was then left to stir at room temperature for 16 h.After completion of the reaction (TLC and MS monitoring), the solutionwas then cooled to 0° C. and the resulting precipitate was filtered toobtain the desired product 44.35 (a-c) as an off-white solid, which wascarried forward to the next step without purification.

1-(2-chloropyridin-3-yl)-4-ethoxy-3,4-dioxobut-1-en-1-olate Lithium Salt(44.35-a)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.85 (s, 1H), 8.58 (m, 1H), 7.38 (m, 1H),6.43 (m, 1H), 4.15 (q, J=7.60 Hz, 2H) and 1.19 (t, J=7.2 Hz, 3H). MS:256.10 (M+H)⁺. Yield: 71%.

4-Ethoxy-1-(5-fluoropyridin-3-yl)-3,4-dioxobut-1-en-1-olate Lithium Salt(44.35-b)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.84 (s, 1H), 8.64-8.65 (m, 1H), 7.84-7.98(m, 1H), 6.39-6.43 (m, 1H), 4.13 (q, J=7.20 Hz, 2H) and 1.20 (t, J=7.2Hz, 3H). MS: 240.29 (M+H)⁺. Yield: quantitative.

4-Ethoxy-3,4-dioxo-1-(pyridazin-4-yl)but-1-en-1-olate Lithium Salt(44.35-c)

MS: 223.22 (M+H)⁺. Yield: 40%.

General Method K2 for the Preparation of Compounds 44.37 (a-c):

To an ice-cold solution of compound 44.35 (a-c) (1.0 eq) in IPA (60 mL)was added (3-fluoro-4-(trifluoromethyl)phenyl)hydrazine hydrochloride44.36 (1.2 eq) and TFA (2.0 eq). The resulting reaction mixture was warmup to room temperature and then stirred at 90° C. for 4-5 h. Aftercompletion of the reaction (TLC monitoring), the solvent was evaporatedand the residue was diluted with water and extracted with ethyl acetate(3 times). The combined organics were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated. The crude waspurified over silica gel (100-200 M, 10-15% EtOAc-hexane) to obtain thedesired product 44.37 (a-c).

Ethyl5-(2-chloropyridin-3-yl)-1-(3-fluoro-4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylate(44.37-a)

¹H-NMR (400 MHz, CDCl₃): δ 8.53-8.55 (m, 1H), 7.52-7.56 (m, 1H),7.37-7.40 (m, 2H), 7.26-7.30 (m, 2H), 7.11 (s, 1H), 4.46 (q, J=7.2 Hz,2H) and 1.41 (t, J=7.6 Hz, 3H). MS: 414.13 (M+H)⁺. Yield: 90%.

Ethyl1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(5-fluoropyridin-3-yl)-1H-pyrazole-3-carboxylate(44.37-b)

¹H-NMR (400 MHz, CDCl₃): δ 8.54 (s, 1H), 8.35 (s, 1H), 7.60-7.64 (m,1H), 7.31-7.36 (m, 2H), 7.05-7.15 (m, 2H), 4.39 (q, J=7.2 Hz, 2H) and1.42 (t, J=6.8 Hz, 3H). MS: 398.20 (M+H)⁺. Yield: 22%.

Ethyl1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(pyridazin-4-yl)-1H-pyrazole-3-carboxylate(44.37-c)

¹H-NMR (400 MHz, CDCl₃): δ 9.26-9.27 (m, 1H), 9.09-9.13 (m, 1H),7.56-7.61 (m, 1H), 7.21-7.32 (m, 3H), 7.05-7.15 (m, 1H), 4.45 (q, J=7.2Hz, 2H) and 1.42 (t, J=7.2 Hz, 3H). MS: 381.29 (M+H)⁺. Yield: 15%.

General Procedure for the Preparation of Compounds 44.38 (a-c):

To an ice-cold solution of ethyl1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate44.37 (a-c) (1.0 eq) in EtOH was added drop wise an aqueous solution ofsodium hydroxide (2.0 eq) in H₂O. The resulting solution was stirred atroom temperature for 2 h. After completion of the reaction (TLCmonitoring), the solvent was evaporated, added H₂O to the residuefollowed by extraction with EtOAc (2×100 mL). The organic layer wasdiscarded and the pH of the aqueous layer was adjusted to ˜4 by adding1N HCl. The resulting precipitate was filtered and dried under vacuum toobtain the desired products 44.38 (a-c) as white solids.

5-(2-Chloropyridin-3-yl)-1-(3-fluoro-4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylicAcid (44.38-a)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.40 (br s, 1H), 8.53-8.54 (m, 1H),8.09-8.11 (m, 1H), 7.85-7.86 (m, 1H), 7.55-7.61 (m, 2H), 7.21-7.23 (m,1H) and 7.13 (s, 1H). LCMS: 386.19 (M+H)⁺, 97.48%. Yield: 55%.

1-(3-Fluoro-4-(trifluoromethyl)phenyl)-5-(5-fluoropyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (44.38-b)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.16 (br s, 1H), 8.67 (s, 1H), 8.60 (s,1H), 7.88-7.92 (m, 1H), 7.74-7.81 (m, 1H), 7.67-7.70 (m, 1H) and7.27-7.34 (m, 2H). LCMS: 368.17 (M−H)⁺, 93.75%. Yield: 90%.

1-(3-Fluoro-4-(trifluoromethyl)phenyl)-5-(pyridazin-4-yl)-1H-pyrazole-3-carboxylicAcid (44.38-c)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.20 (br s, 1H), 9.26-9.28 (m, 2H),7.95-7.99 (m, 1H), 7.75-7.78 (m, 1H), 7.55 (s, 2H) and 7.43-7.45 (m,1H). MS: 353.24 (M+H)⁺. Yield: 43%.

General Method M2 for the Preparation of Compounds of General Structure44.39:

To an ice-cold solution of1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicacid 44.38 (a-c) (1.0 eq) in DMF (2.0 mL) was added DIPEA (2.5 eq) andHATU (1.50 eq). The resulting mixture was stirred under nitrogenatmosphere at 0° C. for 15 min followed by addition of respective amines(1.20 eq). The reaction mixture was then stirred at room temperature for16 h. After the completion of the reaction (TLC monitoring), thesolution was diluted with ice-cold water (30 mL) followed by extractionwith EtOAc (3×50 mL). The combined organics were washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude was purified via prep-HPLC. The yields andanalytical data of the final compounds are set forth in Table 6.16.

TABLE 6.16 Tabulated data of the final compounds including theindividual yields Com- Amine pound Intermediate Yield ¹H-NMR data(DMSO-d₆, 400 ID Structure used (%) LCMS MHz), unless otherwisespecified 317

Int 1.2  6% 617.37 (M + H)⁺, 96.61% δ 8.81 (m, 1H), 8.55 (m, 1H), 8.10(m, 1H), 7.82 (m, 1H), 7.62-7.57 (m, 2H), 7.19 (m, 1H), 7.11 (m, 3H),6.86 (m, 2H), 4.46 (m, 2H), 4.43 (m, 2H), 3.90 (m, 1H), 3.52 (m, 1H),2.24 (m, 2H) and 1.80 (m, 2H) 318

Int 1.2 10% 601.17 (M + H)⁺, 98.88% δ 8.51 (m, 1H), 8.66 (m, 1H), 8.40(m, 1H), 7.82 (m, 2H), 7.67 (m, 1H), 7.33 (m, 1H), 7.21 (s, 1H), 7.08(m, 2H), 6.84 (m, 2H), 4.59 (m, 2H), 4.44 (m, 2H), 3.88 (m, 1H), 3.38(m, 1H), 2.29 (m, 2H) and 1.80 (m, 2H) 319

Int 5.2 25% 605.17 (M − H)⁺, 99.94% δ 11.23 (br s, 1H), 8.65 (m, 1H),8.40 (m, 1H), 7.86 (m, 2H), 7.70 (m, 1H), 7.37 (m, 1H), 7.23 (s, 1H),7.04 (m, 1H), 6.79 (m, 1H), 4.80 (m, 1H), 4.70 (m, 2H), 3.35 (m, 1H),2.97 (m, 1H), 2.14 (m, 2H) and 1.88 (m, 2H) 320

Int 1.2  6% 584.40 (M − H)⁺, 95.72% δ 9.28 (m, 2H), 8.81 (m, 1H), 7.91(m, 1H), 7.89 (m, 1H), 7.57 (m, 1H), 7.42 (m, 2H), 7.01 (m, 2H), 6.85(m, 2H), 4.62 (m, 2H), 4.43 (m, 2H), 3.90 (m, 1H), 3.52 (m, 1H), 2.24(m, 2H) and 1.80 (m, 2H)

Ethyl5-(pyridazin-4-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carboxylate(45.41)

The experimental procedure was similar to the one as mentioned in Scheme43 above (general method K2). ¹H-NMR (400 MHz, CDCl₃): δ 9.25-9.26 (m,1H), 9.09-9.11 (m, 1H), 7.22-7.26 (m, 2H), 7.03-7.07 (m, 2H), 4.46 (q,J=6.8 Hz, 2H) and 1.43 (t, J=7.2 Hz, 3H). MS: 349.22 (M+H)⁺. Yield: 18%.

5-(Pyridazin-4-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carboxylicAcid (45.42)

The experimental procedure was similar to the one as mentioned in Scheme43 above (General method L2). MS: 321.23 (M+H)⁺. Yield: 68%.

General Method M2 for the Preparation of Final Compound 321:

To an ice-cold solution of5-(pyridazin-4-yl)-1-(3,4,5-trifluorophenyl)-1H-pyrazole-3-carboxylicacid 45.42 (1.0 eq) in DMF (2.0 mL) was added DIPEA (2.5 eq) and HATU(1.50 eq). The resulting mixture was stirred under nitrogen atmosphereat 0° C. for 15 min followed by addition of Intermediate 5.2 (1.20 eq).The reaction mixture was then stirred at room temperature for 16 h.After the completion of the reaction (TLC monitoring), the solution wasdiluted with ice-cold water (30 mL) followed by extraction with EtOAc(3×50 mL). The combined organics were washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude residue was purified via prep-HPLC. The yields and analytical dataof the final compound are set forth in Table 6.17.

TABLE 6.17 Tabulated data of the final compounds including theindividual yields Amine Compound Intermediate Yield ¹H-NMR data(DMSO-d₆, 400 ID Structure used (%) LCMS MHz), unless otherwisespecified 321

Int 5.2 13% 554.01 (M + H)+, 99.55% δ 11.23 (br s, 1H), 9.31 (m, 1H),9.21 (m, 1H), 7.64 (m, 2H), 7.46 (m, 2H), 7.04 (m, 1H), 6.79 (m, 1H),4.78 (m, 1H), 4.66 (m, 2H), 3.37 (m, 1H), 2.99 (m, 1H), 2.24 (m, 2H) and1.84 (m, 2H)

Preparation of 4-ethoxy-3,4-dioxo-1-(pyridin-3-yl)but-1-en-1-olateLithium Salt (46.45)

Prepared following the general method J2 (refer to scheme 43). ¹H-NMR(400 MHz, DMSO-d₆): δ 8.95 (s, 1H), 8.61 (d, J=4.0 Hz, 1H), 8.14 (m,1H), 7.44 (m, 1H), 6.40 (m, 1H), 4.12 (q, J=7.20 Hz, 2H) and 1.21 (t,J=7.2 Hz, 3H). MS: 221.95 (M+H)⁺. Yield: 82%.

General Procedure for the Preparation of Compounds 46.46 (a-g):

To an ice-cold solution of4-ethoxy-2-methyl-3,4-dioxo-1-(pyridin-3-yl)but-1-en-1-olate lithiumsalt 46.45 (1.0 eq) in IPA was added respective hydrazine hydrochloride(1.2 eq) and TFA (2.0 eq). The resulting reaction mixture was warm up toroom temperature and then stirred at 90° C. for 4-5 h. After completionof the reaction (TLC monitoring), the solvent was evaporated and theresidue was diluted with water and extracted with ethyl acetate (3times). The combined organics were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated. The crude waspurified over silica gel (100-200 M, 10-15% EtOAc-hexane) to obtain thedesired products 46.46a-g.

Ethyl1-(4-cyano-3-fluorophenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(46.46-a)

¹H-NMR (400 MHz, CDCl₃): δ 8.71-8.72 (m, 1H), 8.62 (s, 1H), 7.61-7.64(m, 2H), 7.44-7.47 (m, 1H), 7.35-7.38 (m, 1H), 7.19 (s, 1H), 7.15-7.17(m, 1H), 4.42 (q, J=7.6 Hz, 2H) and 1.36 (t, J=7.6 Hz, 3H). LCMS: 337.13(M+H)⁺, 96.65%. Yield: 26%.

Ethyl1-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(46.46-b)

¹H-NMR (400 MHz, CDCl₃): δ 8.59-8.66 (m, 1H), 7.77-7.78 (m, 1H), 7.56(d, J=8.04 Hz, 1H) 7.38-7.41 (m, 2H), 7.23-7.25 (m, 1H), 7.21 (s, 1H),7.07-7.10 (m, 1H), 4.48 (q, J=7.2 Hz, 2H) and 1.38 (t, J=7.6 Hz, 3H).MS: 380.22 (M+H)⁺. Yield: 35%.

Ethyl1-(3-fluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(46.46-c)

¹H-NMR (400 MHz, CDCl₃): δ 8.57-8.61 (m, 1H), 7.73-7.75 (m, 1H),7.60-7.63 (m, 1H) 7.37-7.40 (m, 2H), 7.23-7.27 (m, 1H), 7.20 (s, 1H),7.03-7.09 (m, 1H), 4.45 (q, J=6.8 Hz, 2H) and 1.41 (t, J=7.2 Hz, 3H).MS: 380.13 (M+H)⁺. Yield: 40%.

Ethyl1-(4-cyano-2-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(46.46-d)

¹H-NMR (400 MHz, CDCl₃): δ 8.58-8.59 (m, 1H), 8.46 (s, 1H), 8.13 (s,1H), 7.92-7.94 (m, 1H), 7.51-7.57 (m, 2H), 7.31-7.35 (m, 1H), 7.19 (s,1H), 4.44 (q, J=6.8 Hz, 2H) and 1.39 (t, J=7.2 Hz, 3H). MS: 387.12(M+H)⁺. Yield: 39%.

Ethyl1-(2,4-bis(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(46.46-e)

¹H-NMR (400 MHz, CDCl₃): δ 8.56-8.57 (m, 1H), 8.47 (s, 1H), 8.04 (s,1H), 7.77 (d, J=8.0 Hz, 1H), 7.50-7.59 (m, 2H), 7.26-7.32 (m, 1H), 7.18(s, 1H), 4.40 (q, J=7.2 Hz, 2H) and 1.36 (t, J=7.6 Hz, 3H). MS: 430.12(M+H)⁺. Yield: 25%.

Ethyl1-(2-cyano-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(46.46-f)

¹H-NMR (400 MHz, CDCl₃): δ 8.56-8.60 (m, 1H), 8.48 (s, 1H), 8.15 (s,1H), 7.88-7.95 (m, 1H), 7.53-7.58 (m, 2H), 7.30-7.36 (m, 1H), 7.18 (s,1H), 4.41 (q, J=6.8 Hz, 2H) and 1.41 (t, J=7.6 Hz, 3H). MS: 387.09(M+H)⁺. Yield: 35%.

Ethyl1-(4-iodo-3-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate(46.46-g)

MS: 487.90 (M+H)⁺. Yield: 41%.

General Procedure for the Preparation of Compounds 46.47a-g:

To an ice-cold solution of compound 46.46a-g (0.80-1.5 g, 1.0 eq) inEtOH was added drop wise an aqueous solution of sodium hydroxide (3.0eq). The resulting solution was stirred at room temperature for 2-3 h.After completion of the reaction (TLC monitoring), the solvent wasevaporated, added H₂O to the residue followed by extraction with EtOAc(2×100 mL). The organic layer was discarded and the pH of the aqueouslayer was adjusted to ˜4 by adding 1N HCl. The resulting precipitate wasfiltered and dried under vacuum to obtain the desired product 46.47a-gas a white solid.

1-(4-Cyano-3-fluorophenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (46.47-a)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.18 (br s, 1H), 8.59-8.91 (m, 2H),7.67-7.68 (m, 2H), 7.41-7.44 (m, 1H), 7.25-7.27 (m, 2H) and 7.22 (s,1H). MS: 309.11 (M+H)⁺. Yield: 30%.

1-(4-Fluoro-3-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (46.47-b)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.15 (br s, 1H), 8.57-8.58 (m, 2H),7.84-7.86 (m, 1H), 7.60-7.69 (m, 3H), 7.40-7.45 (m, 1H) and 7.24 (s,1H). LCMS: 352.24 (M+H)+, 95.84%. Yield: 73%.

1-(3-Fluoro-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (46.47-c)

LCMS: 352.10 (M+H)⁺, 93.14%. Yield: 67%.

1-(4-Cyano-2-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (46.47-d)

MS: 357.10 (M−H)⁺. Yield: 35%.

1-(2,4-Bis(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (46.47-e)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.16 (br s, 1H), 8.49-8.53 (m, 2H), 8.33(s, 1H), 8.27 (d, J=8.4 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.57-7.59 (m,1H) and 7.35-7.38 (m, 2H). LCMS: 400.30 (M−H)⁺, 99.38%. Yield: 44%.

1-(2-Cyano-4-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (46.47-f)

MS: 357.18 (M−H)⁺. Yield: 28%.

1-(4-Iodo-3-(trifluoromethyl)phenyl)-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylicAcid (46.47-g)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.10 (br s, 1H), 9.03-9.06 (m, 2H), 8.65(s, 1H), 7.70-7.73 (m, 2H), and 7.22-7.33 (m, 3H). LCMS: 460.05 (M+H)⁺,87.11%. Yield: 69%.

General Procedure for the Preparation of Compounds of General Structure48:

To an ice-cold solution of carboxylic acids 46.47a-g (125-150 mg), inDMF (2.0 mL) was added DIPEA (2.5 eq) and HATU (1.50 eq). The resultingmixture was stirred under nitrogen atmosphere at 0° C. for 15 minfollowed by addition of respective amines (1.20 eq). The reactionmixture was then stirred at room temperature for 16 h. After thecompletion of the reaction (TLC monitoring), the solution was dilutedwith ice-cold water (30 mL) followed by extraction with EtOAc (3×50 mL).The combined organics were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The finalcompounds were purified via prep-HPLC. The yields and analytical data ofthe final compounds are set forth in Table 6.18.

TABLE 6.18 Tabulated data of the final compounds including theindividual yields Amine ¹H-NMR data (DMSO-d₆, Compound IntermediateYield 400 MHz), unless otherwise ID Structure used (%) LCMS specified322

Int 1.2 16% 633.14 (M + H)⁺, 98.13% δ 8.79 (m, 1H), 8.54-8.50 (m, 1H),8.51 (m, 1H), 8.33 (s, 1H), 8.22 (m, 1H), 7.88-7.86 (m, 1H), 7.59-7.57(m, 1H), 7.39-7.36 (m, 1H), 7.25 (s, 1H), 7.09-7.03 (m, 2H), 6.83- 6.80(m, 2H), 4.45 (m, 2H), 4.42 (m, 2H), 3.85 (m, 1H), 3.45 (m, 1H),2.30-2.19 (m, 2H) and 1.82-1.69 (m, 2H) 323

Int 1.2 14% 590.19 (M + H)⁺, 98.52% δ 9.40 (m, 1H), 8.85 (m, 2H),8.72-8.70 (m, 1H), 8.50 (m, 1H), 8.15 (s, 1H), 8.09-8.06 (m, 1H), 7.91(m, 1H), 7.74 (m, 1H), 7.24-7.16 (m, 2H), 7.03-6.97 (m, 2H), 4.55 (m,2H), 4.53 (m, 1H), 3.85 (m, 2H), 3.62 (m, 1H), 2.69 (m, 1H) 2.49 (m,1H), 1.92 (m, 1H) and 1.69 (m, 1H) 324

Int 1.2  5% 590.21 (M + H)⁺, 94.61% δ 8.83 (m, 1H), 8.59 (m, 1H),8.54-8.51 (m, 2H), 8.29-8.27 (m, 1H), 7.84 (m, 1H), 7.55 (m, 1H), 7.36(m, 1H), 7.25 (s, 1H), 7.07-7.03 (m, 2H), 6.83- 6.80 (m, 2H), 4.57 (m,2H), 4.42 (m, 2H), 3.82 (m, 1H), 3.50 (m, 1H), 2.22 (m, 2H) 1.81 (m, 1H)and 1.72 (m, 1H) 325

Int 5.2  5% 594.38 (M + H)⁺, 96.36% δ 11.15 (br s, 1H), 8.59 (m, 1H),8.54-8.48 (m, 2H), 8.30 (m, 1H), 7.87 (m, 1H), 7.58 (m, 1H), 7.37 (m,1H), 7.25 (s, 1H), 7.03 (m, 1H), 6.78 (m, 1H), 4.70 (m, 2H), 3.57 (m,2H), 3.23 (m, 1H), 2.94 (m, 1H), 2.14 (m, 1H) 1.90 (m, 1H) and 1.78 (m,1H) 326

Int 1.2  5% 691.08 (M + H)⁺, 92.90% δ 8.81 (s, 1H), 8.60-8.57 (m, 2H),8.16 (m, 1H), 7.70 (m, 2H), 7.44 (m, 1H), 7.28 (m, 1H), 7.12 (m, 3H),6.86 (m, 2H), 4.59 (m, 2H), 4.44 (m, 2H), 3.88 (m, 1H), 3.53 (m, 1H),2.27 (m, 2H) and 1.82 (m, 2H) 327

Int 5.2  5% 695.05 (M + H)⁺, 99.83%. δ 11.24 (br s, 1H), 8.63 (m, 2H),8.19 (m, 1H), 7.79 (m, 1H), 7.72 (m, 1H), 7.48 (m, 1H), 7.32 (m, 1H),7.14 (s, 1H), 7.03 (m, 1H), 6.79 (m, 1H), 4.77-4.67 (m, 3H), 3.35 (m,1H), 2.96 (m, 1H), 2.14 (m, 2H) and 1.89 (m, 2H) 328

Int 6.2 63% 533.14 (M + H)⁺, 99.32% δ 11.60 (br s, 1H), 8.64 (br s, 2H),7.99-8.03 (m, 1H), 7.84 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.66-7.69 (m,1H), 7.43- 7.50 (m, 2H), 7.35 (d, J = 8.40 Hz, 1H), 7.18 (s, 1H), 7.13(d, J = 8.0 Hz, 1H), 4.71-4.85 (m, 2H), 4.54-4.63 (m, 1H), 3.28- 3.35(m, 1H), 2.90-2.96 (m, 1H), 2.32-2.39 (m, 2H) and 1.75-1.86 (m, 2H) 329

Int 2.2 15% 568.24 (M + H)⁺, 98.81% δ 8.83 (br s, 1H), 8.60-8.67 (m,2H), 7.98-8.02 (m, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.59-7.62 (m, 1lH),7.44-7.47 (m, 1H), 7.30 (m, 1H), 7.17 (s, 1H), 6.53-6.59 (m, 2H), 4.55(s, 2H), 4.38 (br s, 2H), 3.48-3.86 (m, 2H), 2.30 (m, 1H), 2.11 (s, 6H),2.15 (m, 1H) and 1.72- 1.80 (m, 2H) 330

Int 4.2 34% 566.18 (M + H)+, 97.01% δ 8.81 (s, 1H), 8.64-8.65 (m, 2H),7.96-8.0 (m, 1H), 7.76 (d, J = 8.40 Hz, 1H), 7.59-7.61 (m, 1H),7.47-7.50 (m, 1H), 7.34 (s, 1H), 7.28-7.30 (m, 1H), 6.91-6.95 (m, 2H),6.72- 6.75 (m, 2H), 5.18 (m, 1H), 4.92 (m, 1H), 4.55 (s, 2H), 2.57-2.75(m, 2H), 2.34-2.38 (m, 2H) and 1.83-1.82 (m, 4H) 331

Int 7.2 23% 613.16 (M + H)+, 99.55% δ 11.30 (br s, 1H), 8.58-8.60 (m,2H), 7.78-7.82 (m, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.60- 7.65 (m, 1H),7.41-7.44 (m, 1H), 7.21 (s, 1H), 7.01-7.06 (m, 1H), 6.77-6.79 (m, 1H),5.31 (t, J = 8 Hz, 1H), 4.87 (t, J = 8.40 Hz, 1H), 4.35-4.42 (m, 1H),2.50 (m, 2H) and 1.84- 2.14 (m, 6H) 332

Int 3.2 22% 651.10 (M + H)+, 99.12% δ 8.94 (s, 1H), 8.58-8.59 (m, 2H),7.80-7.81 (m, 1H), 7.56- 7.71 (m, 3H), 7.41-7.44 (m, 1H), 7.12 (s, 1H),6.83 (m, 2H), 4.63 (s, 2H), 4.40-4.50 (m, 2H), 3.77-3.83 (m, 1H),3.45-3.51 (m, 1H), 2.33-2.59 (m, 2H) and 1.71-1.81 (m, 2H) 333

Int 4.2 16% 609.16 (M + H)+, 99.85% δ 8.79 (s, 1H), 8.60 (m, 2H), 7.76(m, 1H), 7.66-7.71 (m, 2H), 7.56-7.61 (m, 1H), 7.41- 7.44 (m, 1H), 7.28(s, 1H), 6.92-6.96 (m, 2H), 6.74-6.77 (m, 2H), 5.16 (m, 1H), 4.92 (m,1H), 4.54 (s, 2H), 2.49- 2.75 (m, 2H), 2.32-2.34 (m, 2H) and 1.79-189(m, 4H)

Example 2. Biological Activity of Compounds of the Invention

Since TRPA1 functions as a ligand-gated ion channel which is arelatively non-selective cation channel that is calcium permeable, acell-based functional assay that measured increases in intracellularcalcium ([Ca²⁺]_(i)) upon activation with agonist ligands was employedto test unknown compounds. A stable HEK293 cell line that expresseshuman TRPA1 in an inducible manner was employed in this assay. TheseHEK293 cells were grown in Dulbecco's minimal essential mediumcontaining 4.5 mg/ml glucose supplemented with 10% heat-inactivatedfetal bovine serum, 50 units/ml of penicillin, 50 μg/ml of streptomycin,supplemented with 5 μg/ml blasticidin and 50 μg/ml hygromycin B at 37°C. in 95% air 5% CO₂. The expression of TRPA1 was induced by including 1μg/ml doxycycline in the culture medium. For the induced cells,ruthenium red (5 μM) was also added to minimize the constitutive TRPA1channel activity and cells were used 14-18 hrs after induction. Tomeasure [Ca²⁺]_(i) changes, cells were seeded in wells of 96-well platesat ˜100,000 cells/well and grown for 14-18 hrs to reach confluency. Toprevent cell loss from subsequent washing, the wells were treated with20 μg/ml polyornithine (MW>30,000, Sigma, St Louis, Mo.) for >15 min andrinsed once with Hank's balanced salt solution without Mg²⁺ and Ca²⁺. Toload the Ca²⁺ indicator dye, cells were washed once with anextracellular solution (ECS) containing 140 mM NaCl, 5 mM KCl, 1 mMMgCl₂, 1.8 mM CaCl₂, 10 mM glucose, and 15 mM HEPES, pH 7.4 and thenincubated in 50 μL ECS supplemented with 2 μM Fluo4-AM and 0.05%Pluronic F-127 at 37° C. for 60 min. In some experiments, Fluo-8-AM wasused instead of Fluo-4-AM as the calcium-sensitive fluorescent probe.Probenecid (2 mM) was included in all solutions to prevent the leakageof Fluo-4 or Fluo-8 from the cells. At the end of the incubation, cellswere washed three times with ECS and placed in 80 μL of the samesolution. Fluorescence changes were measured using a fluid handlingintegrated fluorescence plate reader, FlexStation (Molecular Devices,Sunnyvale, Calif.). Stock solutions of test compounds were initiallysolubilized in 100% DMSO and then serially diluted to achieve thedesired final concentration. The final concentration of DMSO in theassay did not exceed 0.3% (v/v). Drugs were diluted into ECS at 2× or 3×the desired final concentrations and delivered to the sample plate by anintegrated robotic 8-channel pipettor at preprogrammed time points. TheFluo-4 or Fluo-8 fluorescence was read using the excitation wavelengthof 494 nm and emission wavelength of 525 nm from the bottom of the plateat 0.67 Hz. Experiments were performed at 20-25° C. For certainexperiments, 0.1% BSA was included with the cells and test compounds.

The kinetic data obtained at each test concentration of drug representsa series of fluorescent intensities as a function of time. Data weretransferred from the Softmax Pro software to constructconcentration-response curves for each active compound and curve fittingusing the logistic equation (Prism, Graphpad, San Diego, Calif.) wasused to obtain inhibition constants for antagonists (IC₅₀s) oractivation constants for agonist ligands (EC₅₀s).

Using a sequential addition protocol, test compounds were initiallyapplied to the cells loaded with Fluo-4 or Fluo-8 and fluorescencechanges in each well monitored for 2.5 min. The plate was read again ina kinetic mode after a 15-30 min incubation with the test compoundsafter obtaining baseline values (about 30 s) and subsequent addition ofchallenge with a reference TRPA1 agonist. Reference TRPA1 agonists intesting each compound included at least one of flufenamic acid (FFA),allyl isothiocyanate (AITC) and 4-hydroxynonenal (4-HNE). Compounds thatdemonstrated antagonist activity showed a concentration dependentreduction in initial rate and/or reduction in the magnitude of activitystimulated by the reference agonist.

Antagonist activity can be expressed in terms of IC₅₀ with respect toTRPA1 and agonist activity can be expressed in terms of EC₅₀ withrespect to TRPA1. Results for the TRPA1 modulatory activity of thedisclosed compounds are found below in Table 7; the IC₅₀ values shown inTable 7 were determined from data collected during the time periodinitiated by addition of the reference TRPA1 agonist to the mixturecontaining TRPA1 and the test compound. For each compound, the activityis classified as A, B or C wherein A is an IC₅₀ of 0.001-5 μM; B is anIC₅₀ of 5-25 μM; and C is an IC₅₀ of >25 μM. One of skill in the artwill appreciate that other analytical techniques (e.g., patch clampexperiments as described below) can be used to characterize compoundactivity, and that the IC₅₀ or the EC₅₀ value observed for a particularcompound can vary depending on the technique employed

TABLE 7 TRPA1 modulatory activity of compounds of the disclosure. Cpd #human TRPA1-HEK Activity  6 C  31 C  4 C  12 C  16 B  25 C  28 C  13 C 18 C  29 C  30 C  8 B 143 B 144 B 145 B 146 B 147 C 148 C 152 C 153 C154 C 155 C 156 C 157 C 158 B 159 B 160 C 161 B 162 B 163 B 164 B 165 C166 C 170 C 171 C 172 C 174 C 149 B 150 B 151 C 167 B 168 B 169 C 173 C 54 C  55 A  56 C  57 C  58 C  61 C  62 C  63 C  66 C  67 C  68 C  71 C 74 C  75 C  76 C  79 C  80 C  83 C  84 C  85 C  60 B  65 C  70 B  72 B 73 C  77 A  78 C  82 C  87 C  88 B  89 C  90 C  92 C  93 C  94 C  95 C 96 C  98 B 100 C 101 C 105 C 106 C 107 C  97 C  99 A 102 C 103 C 104 C108 C 109 C 110 C 111 C 114 C 119 C 120 B 121 C 122 C 123 C 124 C 125 C126 C 127 C 128 C 129 C 130 B 131 C 132 C 135 C 136 B 137 C 138 C 139 C140 B 141 B 142 C  69 C  91 C 112 C 113 C 115 C 116 C 117 C 118 C 133 C134 C 177 A 178 B 175 A 176 B  49 A  45 C  52 C  32 C  33 C  34 C  35 C 37 C  38 B  39 C  40 C 179 C 180 A 264 B 259 B 260 A 262 B 198 A 252 B253 A 256 C 267 B 268 A 266 A 263 C 181 A 254 A 255 A 258 C 261 A 257 C265 A 182 A 199 A 212 A 213 A 218 A 219 A 220 A 189 A 185 B 202 A 217 A184 C 201 A 214 A 215 A 183 C 186 A 187 A 200 A 190 A 188 A 191 A 192 A193 A 205 A 216 A 196 A 206 B 210 A 211 A 194 B 195 A 204 A 221 A 197 B209 C 203 C 208 A 222 A 223 A 224 A 207 C  75-b A  75-a A 225 A 226 A227 A 228 A 229 A 230 A 231 A 232 A 233 A 234 A 235 A 236 A 237 A 238 A239 A 240 A 241 A 242 A 243 C 244 B 245 C 246 A 247 C 248 A 249 A 250 C280 A 281 A 282 A 283 B 284 A 272 A 273 A 274 A 285 A 286 A 278 A 289 A290 A 291 A 292 B 295 A 296 A 293 A 301 A 297 A 294 A 298 A 305 A 306 A328 A 324 A 322 A 323 A 331 A 325 A 317 A 320 A 321 A 329 A 330 A 333 A318 A 319 A 326 A 327 A 332 A 313 A 314 A 315 A 316 A

Example 3. Electrophysiological Testing of Compounds of the Invention

Whole-cell patch clamp experiments permit the detection of currentsthrough the TRPA1 channel in the cell line described above. A glasselectrode is brought into contact with a single cell and the membrane isthen ruptured, permitting control of the voltage of the cell membraneand measurement of currents flowing across the membrane using anamplifier attached to the electrode. A perfusion system permits controlof the extracellular solution, including the rapid addition of TRPA1agonists and antagonists that either induce or inhibit the current,respectively. The TRPA1 specific current is activated by application ofa known agonist, selected from a group which consists of flufenamicacid, allyl isothiocyanate (AITC), or 15-deoxy-PGJ2 prostaglandin at theappropriate concentration to the solution. To determine the activity ofcompounds of the present invention, a compound is added before theaddition of an agonist to determine the effects of pre-incubation onTRPA1 activity or alternatively the compound is added simultaneouslywith the agonist to determine the effects of simultaneous addition onTRPA1 activity. Alternatively, an agonist may be added first to activateTRPA1 and a test compound of the present invention added at a timeinterval and for a desired duration thereafter to determine the effectof the test compound on the TRPA1 response.

HEK293 cells expressing human TRPA1 are seeded on polyornithine-treatedglass coverslips one day before patching. Recording pipettes are pulledfrom micropipette glass (World Precision Instruments Inc, Sarasota,Fla.) to 2-4 MΩ when filled with a pipette solution containing (in mM):117 CsCl, 9 EGTA, 1.8 MgCl₂, 14 Tris-creatine phosphate, 4 Mg-ATP, 0.3Tris-GTP, 9 HEPES, pH 7.4 and placed in the bath solution containing (inmM): 150 NaCl, 4 KCl, 2 CaCl₂, 2 MgCl₂, 10 glucose, 10 HEPES, pH 7.4.Isolated cells are voltage-clamped in the whole-cell mode using an EPC10amplifier with data collected at a sampling rate of 5 kHz using ananalog-to-digital converter under the control of PatchMaster (HEKAInstruments). Voltage ramps of 100 ms of −100 mV to +100 mV from theholding potential of −60 mV are applied every 0.5 s. The patched cell iscontinuously superfused by the bath solution through an 8-channelSmartSquirt perfusion system (AutoMate Scientific, Inc., Berkeley,Calif., USA). Compounds are diluted in the final concentration andapplied for 10-40 sec as desired. For either kinetic orconcentration-response studies, the application of reference agonist is10 sec and the maximal current densities at −100 and +100 mV are usedfor calculations. All recordings are performed at room temperature (˜23°C.).

Example 4. Compound Activity in Freund's Complete Adjuvant HyperalgesiaModel

The efficacy of compounds of the disclosure in reducing or alleviatinginflammatory pain is tested using an established animal model fortesting potential analgesic activity of compounds that is widely knownas the Freund's Complete Adjuvant (CFA) model of hyperalgesia. The CFAmodel is a well-established acute inflammatory pain model widely used bythe pharmaceutical industry to evaluate the analgesic activity ofcompounds including TRPA1 antagonists (Eid, S R, et al. (2008)“HC-030031, a TRPA1 selective antagonist attenuates inflammatory- andneuropathy-induced mechanical hypersensitivity.” Mol Pain 4:48-58.)

Testing employs the Randell-Selitto test or paw pressure test which is atechnique for the measurement of the pain response in animals. For thisinflammatory pain model, rats are injected with 200 μl of CompleteFreund's Adjuvant (CFA), 1:1 in saline intraplantarly into their leftpaw (Colpaert, 1987). Animals are tested for hyperalgesia 3 days afterCFA administration, using withdrawal threshold to paw pressure(Randal-Selitto test). To investigate whether the anti-hyperalgesiceffect of the test compound are observed upon repeated dosing, thecompound is administered for 3 days at a range of doses which include0.3, 1, 3, 10 and 30 mg/kg by either oral or i.p. administration eachday. Reversal of mechanical hyperalgesia is assessed at the timecorresponding to the peak plasma levels of each drug (determined inseparate pharmacokinetic experiments) after oral or i.p. dosing for thetest compound (1-7 hrs) post-dose on day 1, 2 and 3. Either naproxen,indomethacin, and diclofenac (3-30 mg/kg PO) can be included as apositive control test agent. Compounds of the disclosure which haveefficacy in this model diminish pain responses compared to responses inthe absence of the compound.

Example 5. Compound Activity in Spinal Nerve Ligation Neuropathic PainModel

This example describes the use of an animal model for testing compoundsof the disclosure for their ability to reduce neuropathic pain. For theneuropathic pain model (spinal nerve ligation, SNL) also known as theChung model, rats are anesthetized with isoflurane and placed on aheating pad. Using aseptic techniques, the L5 and L6 spinal nerves areexposed, ligated and transected (Kim, S. H. and Chung, J. M, (1992),Pain, 50 (3): 355-363). Muscle and skin are closed with 4-0 Polydiaxoneand wound clips, respectively. Allodynia is assessed 2-4 weeks post SNLsurgery and only rats that develop allodynia as defined by a significantdecrease in their mechanical threshold using von Frey filaments areused. Tactile allodynia is assessed with calibrated von Frey filaments(Stoelting Co, Wood Dale, Ill.), using an up-down paradigm (Chaplan, S.R., et al. (1994) J. Neurosci. Methods, 53 (1): 55-63). Pregabalin (3-30mg/kg PO) or gabapentin (50-100 mg/kg PO or 100-150 mg I.P) is includedas a positive control.

Test compounds are administered to the surgically treated rats eitherorally or I.P, and pain measurements are assessed at post-dosingintervals that correspond to near-maximal peak plasma concentrations forthe test compound and specific mode of administration.

The action of test compounds 175, 180, and 198 was evaluated in theChung model after surgery to induce neuropathy. Test compounds wereadministered to the surgically treated rats 18 days after L5-L6 spinalnerve injury at 30 mg/kg i.p (10 ml/kg). Gabapentin at 150 mg/kg i.p.(10 ml/kg) was administered as a positive control group. Vehicle andtest compounds were dissolved in 10% DMSO, 20% Tween-80 and 40% PEG-400.On the day before treatment, the neuropathic pain basal response wasmeasured by von Frey test and the rats were randomized based on PWTresponses. A cut-off of <4.0 g was considered before selection ofanimals for treatment. On the day of treatment, the test compounds wereadministered at 30 mg/kg i.p. (10 ml/kg) dissolved in 10% DMSO, 20%Tween-80, 40% PEG-400. Additional test groups included vehicle controland gabapentin at 150 mg/kg i.p. (10 ml/kg). The mechanical allodyniawas measured at 2 hrs post-dose. Results for compound 175 are shown inFIGS. 1 and 2 where data are presented as paw withdrawal threshold (PWTin g) (FIG. 1) and percentage of maximal possible effect (% MPE) (FIG.2). Each bar represents the mean±SEM of 8 rats. The test compoundsdemonstrated significant anti-allodynic effect on paw withdrawalthreshold and % MPE (p<0.001). Statistical analysis was completed usingone-way ANOVA followed by Dunnett's post-test. % MPE values exhibited bythe test compounds are set forth in Table 8.

TABLE 8 Efficacy of Algomedix Compounds in the Spinal Nerve LigationModel of Neuropathic Pain Compound No. Dose % MPE 175 30 mg/kg, i.p  59± 10 (3) 180 30 mg/kg, i.p. 65 (1) 198 30 mg/kg, i.p. 41 (1) % MPE = %Maximum Possible Effect ( ) number of experiments

The test compounds inhibited allodynia and hyperalgesia while thevehicle administered group did not show any improvement. Statisticalanalysis showed the differences between the vehicle and test compoundgroup to be highly significant. From these results, the test compoundsshowed a high level of effectiveness (41-65% of maximal possible effect)for reducing neuropathic pain.

Example 6. Compound Activity in Incisional Pain Model

The effects of compounds of the disclosure on post-surgical pain areassessed using an incisional pain model, as described previously byBrennan et al. (1996). In the incisional pain model, Sprague-Dawley rats(weighing 200-300 g) undergo surgery by having a 1 cm longitudinalincision made through skin and fascia of the plantar aspect of the paw.Unoperated rats serve as controls. Hind paw withdrawal thresholds (PWTs)to a noxious mechanical stimulus are determined using an analgesimeter.Withdrawal responses to punctuate mechanical stimulation are determinedby using calibrated von Frey filaments. Cut-off is set at 250 g and theendpoint is taken as complete paw withdrawal. Twenty-four hoursfollowing plantar incision, predrug PWTs are measured, and the rats(9-20/group) receive a single dose of 3, 10 or 30 mg/kg p.o. or i.p. thetest compound, 30 mg/kg p.o. celecoxib as a positive control, orvehicle. PWTs are determined again at multiple intervals (eg. at 1, 3, 5and 24 hours) postdrug administration. The percent reversal ofhyperalgesia for each animal is calculated by (Postdosethreshold−predose threshold)/(Baseline threshold−predose threshold)×100.

Example 7. Compound Activity in Iodoacetate Osteoarthritic Pain Model

An established animal model of osteoarthritis related pain has beentermed the iodoacetate model since it is based upon the progressivejoint destruction which occurs after injection of iodoacetate into thearticular space of the knee of the rat (Marker and Pomonis, 2012). Painrelated behaviors that can be measured include both hind limb weightbearing and primary mechanical hyperalgesia. In the rat model ofosteoarthritis, iodoacetate (IOA, 2 mg/25 μL per rat in pH 7.4 saline)is administered under brief isoflurane anesthesia into the rat left kneejoint and hypersensitivity to von Frey filaments and changes in weightbearing is assessed 6 weeks post-IOA administration. Rats receive asingle dose of 1, 3, 10 or 30 mg/kg p.o. or i.p. of the test compoundadministered prior to testing at an interval determined by the timerequired to reach peak plasma levels for the individual test agent.Percent reversal of hypersensitivity is calculated as:(post-drug−post-IOA injection)/(pre-IOA injection−post-IOAinjection)×100, where 100% is equivalent to complete reversibility.

Example 8. Compound Activity in Formalin Nociceptive Pain Model

The formalin model is widely used for evaluating the effects ofanalgesic compounds in laboratory animals. It is a useful model fornociceptive pain. In this test, a dilute (0.5-5%) formalin solution (inwhich formaldehyde is the active ingredient) is injected into the paw ofa rodent, and pain-related behaviors are assessed over two temporallydistinct phases, including an initial robust phase in which paw lifting,licking, and flinching are scored during the first 10 min, followed by atransient decline in these behaviors and a subsequent second phase ofbehavior lasting 30-60 min.

For the formalin-induced model, mice or rats are administered withformalin and/or one of the disclosed compounds. Test compounds areeither injected intradermally, delivered orally or by i.p.administration 30-120 min prior to formalin injection. Formalin is theninjected (50 μl of 2.5% formalin, diluted in saline) into the dorsalsurface of the right hind paw of the rat, and the animal is put into achamber of an apparatus where movement of the formalin-injected paw isrecorded. The number of paw flinches or paw licking and biting istallied by minute over the next 60 min. In some analyses of collecteddata, the 60 minute observation period is subdivided into variousphases.

Example 9. Compound Activity in Chronic Constriction Injury NeuropathicPain Model

The rat chronic constriction injury (CCI) model of neuropathic paindeveloped by Bennett and Xie (1988) is a neuropathic pain model widelyused to assess analgesic activity of test compounds. Subsequent toligation of the sciatic nerve, eventual damage of peripheral nervesoccurs in part due to production of several inflammatory mediators(e.g., proinflammatory cytokines and chemokines) which contribute togeneration and maintenance of neuropathic pain.

The surgery protocol used for generating CCI rats is described byBennett and Xie (Bennett, G J, Xie, Y K (1988) Pain 33(1): 87-107.). Inbrief, male Sprague-Dawley rats (175-250 g) are anesthetized, the middlethird of the right sciatic nerve is exposed through a 1.5 cmlongitudinal incision and three ligatures (5-0 chromic Catgut) are tiedloosely around the sciatic nerve proximal to the sciatic trifurcation.Incisions are then sutured and closed, rats are administered antibioticand general health is evaluated daily during the recovery. Two weekspost-nerve ligation, basal mechanical allodynia is measured as describedfor the rat Chung model and CCI rats using paw withdrawal thresholds(PWT)<4 g to qualify rats for inclusion in the study (Kim, S H, Chung, JM (1992). Pain 50(3): 355-363; Chaplin, S R, et al. (1994) J NeurosciMethods 53(1): 55-63).

On the following day, compounds of the invention are solubilized in apre-validated vehicle and administered at doses of 1, 3, 10 and 30 mg/kg(oral or i.p.) and PWTs are measured during a period corresponding topeak plasma levels of the compound. Each experimental group consists of8 rats. Gabapentin is used as a positive control group and theexperimenter recording behavior is blinded to the treatment groups. The50% PWT and % maximal possible effect data are analyzed using one-wayANOVA followed by the Dunnett post-test using Prism (Graphpad).

Example 10. Compound Activity in Streptozotocin Diabetic NeuropathicPain Model

Diabetes related damage to sensory nerves (diabetic neuropathy) is acommon complication of Type 1 and Type 2 diabetes and people with thisneuropathy suffer from chronic pain. The injection of streptozotocin(STZ) into rats is a commonly used chemical method to induce a diabeticcondition leading to diabetic neuropathic pain. The STZ neuropathic painmodel is commonly used to evaluate the efficacy of anaglesic compounds,including TRPA1 antagonists (Courteix, C, et al. (1994) Pain 57(2):153-160; Wei, H, et al. (2009) Anesthesiology 111: 147-154.) After STZadministration, hyperglycemia and hypoinsulinemia appear and persist dueto irreversible toxicity.

The efficacy of compounds of the invention for inhibiting or reducingdiabetic neuropathic pain and reducing pain hypersensitivity aredetermined in this model using the following established procedure. Inbrief, male Sprague-Dawley rats (175-200) grams are administered STZ (45mg/kg i.v. in 0.1M citrate buffer) into the dorsal tail vein and,hyperglycemia is confirmed by measuring glucose levels 3, 10 and 17 daysafter STZ administration. Mechanical allodynia generally appears threeweeks post injection of STZ and lasts for approximately seven weeks. Onday 17 after STZ administration, basal mechanical allodynia is measuredas described for the rat SNL model and rats displaying 50% PWT values of<5 g qualify for the investigation. The next day, compounds of theinvention are solubilized in pre-validated vehicle and administered atdoses of 1, 3, 10 and 30 mg/kg (oral or i.p.) to qualified rats.Mechanical allodynia is measured as described for the Chung model attime corresponding to the period when peak plasma levels for the studycompound are observed. Each experimental group will include eight ratsand tramadol (30 mg/kg, i.p.) will be used as a positive control. The50% PWT and % MPE data are analyzed using one-way ANOVA and post-hocDunnett's test using the computer program, Prism (Graphpad).

Example 11. Compound Activity in Chemotherapy-Induced Neuropathic PainModel

Chemotherapy-induced peripheral neuropathy is one of the most seriouscomplications of anti-cancer drug therapy. For example, agents whichinclude paclitaxel (Taxol) or oxaliplatin which are most effective andfrequently used chemotherapeutics produce peripheral neurotoxicity withpatients reporting neuropathic pain during and often persisting afterchemotherapeutic treatment. The TRPA1 antagonist, AD_09, has beenreported to reduce neuropathic pain in the oxaliplatin model (Nativi, C,et al. (2013) Scientific Reports 3, 2005, 1-10.)

The studies described below provide a method to test compounds of thepresent invention in the established rat model of paclitaxel-inducedneuropathic pain (Flatters, S J and Bennett, G, Pain (2004) 109:150-161)and provide evidence for efficacy for one compound of the presentinvention. In this procedure, male Sprague-Dawley rats received i.p.injections of 1 mg/kg paclitaxel or vehicle solution every other day fora total of 4 injections (Day 0, 2, 4 and 6). After receiving injectionson even-number experimental days, the rats were tested for mechanicaland cold allodynia on odd-number experimental days. After the fulldevelopment of allodynia after the last paclitaxel injection on day 11,one subgroup of the rats (7 rats per treatment group) received an oraldose or i.p. injection of compound of the present invention (e.g., 1, 3,10 or 30 mg/kg) or its vehicle solution. On the day of treatment, thetest compound was administered at 10 mg/kg i.p. (2 ml/kg) dissolved in10% DMSO, 20% Tween-80, 40% PEG-400. Additional test groups includedvehicle control and gabapentin at 10, 30 and 100 mg/kg i.p. (2 ml/kg).The mechanical allodynia was measured at 2 hrs post-dose for compound271. Mechanical allodynia was measured using the Von Frey filaments todetermine the paw withdrawal threshold for each animal and assess theeffects of the test compound-s to reduce pain. Rats were tested formechanical and/or cold allodynia 1 hour after dosing.

Rats can be tested at approximately 2 hour intervals thereafter (timeinterval dependent on the effect) as long as the effect of TRPA1antagonist lasts. In some cases, more than one treatment of the compoundof the present invention (TRPA1 antagonist) can be given before or afterthe effect of the previous dose subsides to provide repetitive dosingregimens.

The test compound #271 demonstrated significant anti-allodynic effect onpaw withdrawal threshold and demonstrated a 49.1% MPE for reversingpaclitaxel induced neuropathic pain. One-way ANOVA followed by Dunnet'spost-test was used for statistical analysis of the data for Compound#271 and percentage change in the maximal possible effect wassignificant at the p<0.05. The magnitude of the effect on neuropathicpain in this model was greater than the gabapentin at the same dose,34.8% MPE, at 10 mg/kg.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference.

Although the foregoing has been described in some detail by way ofillustration and example for purposes of clarity of understanding, itwill be readily apparent to one of ordinary skill in the art in light ofthe disclosed teachings that certain changes and modifications may bemade thereto without departing from the spirit or scope of thedisclosure.

The invention claimed is:
 1. A compound having the following formula,

or a pharmaceutically acceptable salt thereof, or an isotopic variantthereof, wherein: Z¹ Z², Z³, Z⁴, and Z⁵ are each independently selectedfrom the group consisting of N, CH, and CR^(a); or Z¹ and X, togetherwith atoms in the rings to which they are attached, form an additionalfused, five- to eight-membered cycloalkyl or heterocyclyl ring with from0 to 4 R^(z) substituents; wherein at least one of Z², Z³, and Z⁴ is Nwherein 0, 1, or 2 of Z², Z³, and Z⁴ is N; Y¹, Y², Y³, Y⁴, and Y⁵ areeach independently selected from the group consisting of N, CH, andCR^(b); wherein 0, 1, or 2 of Y¹, Y², Y³, Y⁴, and Y⁵ is N each R^(a) andR^(b) is independently selected from the group consisting of cyano,carboxyl, C₁-C₄ alkyl, C₁-C₄ hydroxyalkyl, C₃-C₈ cycloalkyl, C₁-C₄alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, halo, amino, C₁-C₆alkylamino, C₁-C₆ amido, C₁-C₄ alkyloxycarbonyl, C₁-C₆ alkylsulfonyl,and hydroxyl; or, alternatively, two adjacent R^(a) or two adjacentR^(b), together with the atoms to which they are attached, form anadditional fused aryl, heteroaryl, cycloalkyl, or heterocyclyl ring withfrom 0 to 4 R^(z) substituents; each R^(Z) is independently selectedfrom the group consisting of halo, C₁-C₃ alkyl, C₁-C₃ haloalkyl, andC₁-C₃ alkoxy; X is N or CR^(d); R^(d) is selected from the groupconsisting of hydrogen, halo, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, C₁-C₄ haloalkoxy, C₃-C₆ cycloalkyl, and C₃-C₆ cycloalkoxy; W¹,W², W³, and W⁴ are each C(R^(f))₂; each R^(f) is independently selectedfrom the group consisting of hydrogen, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl,and halo; or two axial R_(f) substituents of a pair of W^(n) selectedfrom the group consisting of (W¹ and W²), (W² and W³), and (W³ and W⁴)join to form a —(C(R^(z))₂)_(t)— bridge or a —(CH₂)_(t)— bridge; t is aninteger selected from 2 and 3; Q is selected from the group consistingof C(R^(e))(D), F, and G; R^(e) is selected from the group consisting ofhydrogen, C₁-C₃ alkyl, and C₁-C₃ fluoroalkyl; D is a bicyclic group ofFormula Id,

F is a spirocyclic group of Formula If,

G is a bicyclic spirocyclic group of Formula Ig,

L² and L³ are each independently selected from C═O and C═S; Y⁶, Y⁷, Y⁸,Y⁹, and Y¹⁰ are each independently selected from the group consisting ofN, CH, and CR^(b); wherein 0, 1, or 2 of Y⁶, Y⁷, Y⁸, Y⁹ and Y¹⁰ is N andR^(c) is selected from the group consisting of hydrogen, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₃-C₆ cycloalkyl, (C₃-C₆ cycloalkyl)C₁-C₃ alkyl, andC₁-C₇ acyl.
 2. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, or an isotopic variant thereof, wherein: each R^(f) isindependently selected from the group consisting of hydrogen, C₁-C₃alkyl, C₁-C₃ fluoroalkyl, and halo.
 3. The compound of claim 2, or apharmaceutically acceptable salt thereof, or an isotopic variantthereof, wherein: each R^(f) is independently selected from the groupconsisting of hydrogen and C₁-C₃ alkyl.
 4. The compound of claim 1, or apharmaceutically acceptable salt thereof, or an isotopic variantthereof, wherein: X is CR^(d); and R^(d) is selected from the groupconsisting of hydrogen, halo, and C₁-C₄ alkyl.
 5. The compound of claim1, or a pharmaceutically acceptable salt thereof, or an isotopic variantthereof, wherein:

is a cyclic group selected from

u is an integer from 0 to
 4. 6. The compound of claim 5, or apharmaceutically acceptable salt thereof, or an isotopic variantthereof, wherein: each R^(a) is independently selected from the groupconsisting of cyano, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, halo, C₁-C₆ amido, and hydroxyl.
 7. The compound of claim 5,or a pharmaceutically acceptable salt thereof, or an isotopic variantthereof, wherein:

is a cyclic group selected from


8. The compound of claim 1, or a pharmaceutically acceptable saltthereof, or an isotopic variant thereof, wherein:

is a cyclic group selected from

v is an integer from 0 to
 5. 9. The compound of claim 8, or apharmaceutically acceptable salt thereof, or an isotopic variantthereof, wherein: each R^(b) is independently selected from the groupconsisting of cyano, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, halo, C₁-C₆ alkylamino, amino, C₁-C₆ amido, and hydroxyl.10. The compound of claim 8, or a pharmaceutically acceptable saltthereof, or an isotopic variant thereof, wherein:

is a cyclic group selected from


11. The compound of claim 1, or a pharmaceutically acceptable saltthereof, or an isotopic variant thereof, wherein: Q is C(R^(e))(D); D isselected from the group consisting of

r is 0 to 4; each R^(b) is independently selected from the groupconsisting of cyano, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, and halo; R^(e) is hydrogen; and R^(c) is hydrogen or C₁-C₄alkyl.
 12. The compound of claim 11, or a pharmaceutically acceptablesalt thereof, or an isotopic variant thereof, wherein: D is selectedfrom the group consisting o


13. The compound of claim 1, or a pharmaceutically acceptable saltthereof, or an isotopic variant thereof, wherein: Q is F; F is aspirocyclic group selected from

and

Y⁶, Y⁷, Y⁸, Y⁹, and Y¹⁰ are each independently selected from the groupconsisting of N, CH, and CR^(b) wherein 0, 1, or 2 of Y⁶, Y⁷, Y⁸, Y⁹ andY¹⁰ is N; each R^(b) is independently selected from the group consistingof cyano, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy,and halo; and R^(c) is selected from the group consisting of hydrogenand C₁-C₄ alkyl.
 14. The compound of claim 13, or a pharmaceuticallyacceptable salt thereof, or an isotopic variant thereof, wherein:

is selected from the group consisting of


15. The compound of claim 1, or a pharmaceutically acceptable saltthereof, or an isotopic variant thereof, wherein: Q is G; G is

Y⁶, Y⁷, Y⁸, and Y⁹ are each independently selected from the groupconsisting of N, CH, and CR^(b) wherein 0, 1, or 2 of Y⁶, Y⁷, Y⁸, and Y⁹is N; each R^(b) is independently selected from the group consisting ofcyano, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄haloalkoxy, andhalo; and R^(c) is selected from the group consisting of hydrogen andC₁-C₄ alkyl.
 16. The compound of claim 15, or a pharmaceuticallyacceptable salt thereof, or an isotopic variant thereof, wherein: G isselected from the group consisting of


17. The compound of claim 1, or a pharmaceutically acceptable saltthereof, or an isotopic variant thereof, wherein the compound isselected from:


18. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1, or a pharmaceutically acceptable saltthereof, and at least one pharmaceutically acceptable carrier,excipient, or diluent.
 19. A method of treating pain comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of claim 1, or a pharmaceutically acceptable saltthereof.
 20. The method of claim 19, wherein said pain is selected fromthe group consisting of acute pain, chronic pain, inflammatory pain,neuropathic pain, diabetic peripheral neuropathic pain,chemotherapeutic-induced peripheral neuropathic pain, nociceptive pain,and periprocedural pain.
 21. The method of claim 19, further comprisingadministering a second therapeutic agent for the treatment of pain orinflammation.